microrna-29 fine-tunes the expression of key foxa2 ... · 1 microrna-29 fine-tunes the expression...
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microRNA-29 fine-tunes the expression of key FOXA2-activated lipid metabolism genes
and is dysregulated in animal models of insulin resistance and diabetes
Short running title: A role for miR-29 in hepatic lipid metabolism
C. Lisa Kurtz1,!
, Bailey C. E. Peck1,2,!
, Emily E. Fannin1, Carine Beysen
3, Ji Miao
4, Stuart R.
Landstreet5, Shengli Ding
6, Vandana Turaga
1, P. Kay Lund
6, Scott Turner
3, Sudha B. Biddinger
4,
Kasey C. Vickers5 and Praveen Sethupathy
1,2,*
1Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill,
Chapel Hill, NC, USA
2Genetics and Molecular Biology Curriculum, University of North Carolina at Chapel Hill,
Chapel Hill, NC, USA
3KineMed, Inc., Emeryville, CA, USA
4Department of Pediatrics, Boston Children’s Hospital, Boston, MA, USA
5Department of Medicine, School of Medicine, Vanderbilt University, Nashville, TN, USA
6Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
� These authors contributed equally to this work.
* Correspondence should be addressed to:
Praveen Sethupathy, Ph.D.
120 Mason Farm Rd.
5091 Genetic Medicine Bldg.
Chapel Hill, NC 27599-7264
Office: 919-966-6387
Fax: 919-843-4682
Word Count: 3092
Number of Figures: 5
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Diabetes Publish Ahead of Print, published online April 10, 2014
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Abstract
microRNAs (miRNAs) have emerged as biomarkers of metabolic status, etiological factors in
complex disease, and promising drug targets. Recent reports suggest that miRNAs are critical
regulators of pathways underlying the pathophysiology of type 2 diabetes. In this study, we
demonstrate by deep sequencing and real time quantitative PCR that hepatic levels of Foxa2
mRNA and miR-29 are elevated in a mouse model of diet-induced insulin resistance. We also
show that Foxa2 and miR-29 are significantly up-regulated in the livers of Zucker Diabetic Fatty
(fa/fa) rats and that the levels of both returned to normal upon treatment with the insulin-
sensitizing agent Pioglitazone. We present evidence that miR-29 expression in human hepatoma
cells is controlled in part by FOXA2, which is known to play a critical role in hepatic energy
homeostasis. Moreover, we demonstrate that miR-29 fine-tunes FOXA2-mediated activation of
key lipid metabolism genes, including PPARGC1A, HMGCS2, and ABHD5. These results
suggest that miR-29 is an important regulatory factor in normal metabolism and may represent a
novel therapeutic target in type 2 diabetes and related metabolic syndromes.
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Type 2 diabetes is characterized in part by resistance to insulin action in the liver and
other metabolic tissues(1). microRNAs (miRNAs) are widely recognized as important regulators
of a diverse array of biological processes(2), including metabolism(3). Recently, miRNAs have
also emerged as stable plasma biomarkers of physiologic and metabolic status(4; 5), etiological
factors in complex disease(6), and promising therapeutic targets(7; 8). miRNA-mediated gene
regulation occurs principally at the post-transcriptional level and has been the subject of intense
research over the past decade. Several miRNAs have been implicated in the pathobiology of a
variety of metabolic disorders, including type 2 diabetes(9), cardiovascular disease(10), and
obesity(11). Recently, we reported that miR-27b is a post-transcriptional regulatory hub in liver
lipid metabolism and is altered in dyslipidemia(12). Another group of studies demonstrated that
miR-33 modulates lipoprotein metabolism in mice(13-17) and non-human primates(18), as well
as insulin signaling in cultured human hepatocytes(19). And, most recently, both miR-103/107
and miR-802(20) were shown to regulate insulin sensitivity and glucose tolerance in mice(20;
21). These findings strongly support the notion that miRNAs are critical players in pathways that
underlie metabolic disease etiology, thus raising the possibility that miRNA-based therapy could
be relevant for type 2 diabetes and related metabolic syndromes.
miR-29 has been demonstrated to be an important regulator of numerous biological
processes, including neuronal maturation(22), fibrosis(23), hematopoiesis(24), replicative
senescence(25), and immune response(26). Our recent in silico work identified miR-29 as the
strongest candidate miRNA regulatory hub in the type 2 diabetes gene network(27). Other
groups have shown that miR-29 is highly responsive to glucose and may regulate beta cell
proliferation and insulin secretion(28; 29). We sought to investigate miR-29 in the liver, which
is a metabolic tissue of critical relevance to type 2 diabetes etiology.
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In this study, we demonstrate that: (1) hepatic miR-29 and Foxa2 mRNA are significantly
up-regulated in two different animal models of insulin resistance; (2) the insulin-sensitizing drug
Pioglitazone corrects hepatic miR-29 and Foxa2 levels in the Zucker Diabetic Fatty (ZDF) rat
model of diabetes; (3) miR-29 levels in hepatocytes are controlled in part by the insulin-
regulated transcription factor FOXA2; and (4) miR-29 fine-tunes FOXA2-mediated regulation of
key lipid metabolism genes. Taken together, our findings implicate miR-29 as an important
regulatory factor for lipid homeostasis, and motivate future studies to investigate the utility of
miR-29 as a tissue biomarker of type 2 diabetes drug efficacy, as well as a potential therapeutic
target in metabolic syndromes.
Research Design and Methods
Animal studies
Female C57BL/6J mice were from a UNC Chapel Hill colony and started at 4 weeks of
age on high-fat diet (D01060502, 45% kcal from fat) or matched low-fat diet (D01060501, 10%
kcal from fat) (Research Diets, New Brunswick, NJ). Livers were isolated after 16 weeks of diet
and RNA was isolated using the Norgen Total RNA Purification kit (Thorold, ON, Canada).
Male Zucker Diabetic Fatty (ZDF) rats (Charles Rivers) were acclimated for two weeks and had
access to a standard chow diet (Lab Diet). Four weeks of Pioglitazone treatment (30 mg/kg/day)
started at 8 weeks of age. Blood was collected once per week during treatment in order to
measure glucose levels. Livers were isolated at 12 weeks of age and RNA was isolated using
TRiZol.
Cell culture
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Huh7 cells (human hepatoma) were obtained from Dr. Stanley Lemon’s laboratory at
UNC Chapel Hill. Huh7 cells were maintained in 5 mM glucose DMEM (Sigma-Aldrich, St.
Louis, MO) supplemented with 10% FBS, 2 mM L-glutamine, 1 mM Na-pyruvate and 1X
NEAA (Invitrogen, Grand Island, NY), in 100 mm collagen 1 coated cell culture dishes (Becton-
Dickinson, Bedford, MA). For transfections, cells were split into 6 well collagen 1 coated plates
(Becton-Dickinson) to approximately 70-80% confluency, and allowed 24 hours to adhere. All
cells were cultured in a humidified incubator at 37oC and 5% CO2.
Transfection studies
Huh7 cells were plated on collagen 1 coated 6-well plates (Becton-Dickinson, Bedford,
MA) 1 day before transfection. At ~70-80% confluency, the cells were transfected with either 10
nM miRIDIAN hsa-miR-29a mimic (ThermoScientific; Waltham, MA), 10 nM mmu-miR-29a-
3p LNA inhibitor (Exiqon; Woburn, MA), or 100 nM ON-TARGET plus human siRNA against
FOXA2 (ThermoScientific; Waltham, MA) using either Dharmafect 4 (ThermoScientific;
Waltham, MA) or Lipofectamine 2000 (Life Technologies, Grand Island, NY) transfection
reagent. A human FOXA2 expression vector containing FOXA2 transcript variant 1 in the
pCMV6-XL5 plasmid (Origene, Rockville, MD) was transfected (1ug) using Dharmafect Duo
transfection reagent (ThermoScientific; Waltham, MA). Forty-eight hours after transfection, total
RNA was isolated from the cells using the Total RNA Purification Kit from Norgen (Thorold,
ON, Canada).
Small RNA sequencing analysis
Total RNA was extracted from mouse liver tissue using the Norgen total RNA
purification kit (Norgen; Thorold, ON, Canada). RNA quality was assessed by Agilent 2100
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Bioanalyzer, and only very high quality samples with RNA Integrity Number (RIN) above 8.0
were considered further. Small RNA libraries (n=2 for each of HFD-fed and LFD-fed mice) were
generated using the Illumina TruSeq small RNA library preparation kit. These libraries were then
sequenced on the Illumina HiSeq 2000 platform (50 bp reads). miRNA and isomiR
identification and quantitation was performed as described previously(27).
Gene expression (RNA) analysis
Total RNA was isolated from cultured Huh7 cells or mouse liver tissue using the Total
RNA Purification kit (Norgen; Thorold, ON, Canada), and subject to DNase treatment using the
TURBO DNA-free kit (Applied Biosystems; Grand Island, NY). Complementary DNA (cDNA)
was synthesized using either the TaqMan microRNA Reverse Transcription kit (Applied
Biosystems; Grand Island, NY) or the High Capacity RNA to cDNA kit (Applied Biosystems;
Grand Island, NY) according to the manufacturer’s instructions. Real-time PCR amplification
was performed using TaqMan miRNA or gene expression assays in TaqMan Universal PCR
Master Mix (miRNA qPCR) or TaqMan Gene Expression Master Mix (gene expression qPCR)
on a BioRad CFX96 Touch Real Time PCR Detection system (Bio-Rad Laboratories, Inc.,
Richmond, CA). Reactions were performed in triplicate using either U6 (miRNA expression) or
RPS9 (gene expression) as the internal control. miRNA and mRNA levels were expressed as
relative quantitative values (RQVs). All TaqMan assays used in this study where purchased from
Applied Biosystems, Inc. (Grand Island, NY) and include: miR-29a (4427975, 002112), miR-
29b (4427975, 000412), miR-29c (444087, 000587), miR-15a (4427975, 000389), U6 (4427975-
001973), RPS9 (human – 4331182, Hs02339424_g1; mouse – 4331182, Mm00850060_s1),
ABHD5 (4331182, Hs01104373_m1), HMGCS2 (4331182, Hs00985427_m1), G6PC (human –
4331182, Hs00609178_m1; mouse – 4331182, Mm00839363_m1), PPARGC1A (4331182,
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Hs01016719_m1), and FOXA2 (human – 4331182, Hs00232764_m1; mouse – 4331182,
Mm01976556_s1; rat – 4331182, Rn0145600_m1).
Western blotting
Protein was isolated forty-eight to seventy-two hours after transfection. RIPA buffer
(Sigma Aldrich, St. Louis, MO), supplemented with complete protease inhibitor (Roche,
Indianapolis, IN), phosphatase inhibitor (ThermoScientific, Waltham, MA), 100 mM PMSF in
100% isopropanol, 0.1% beta-mercaptoethanol (VWR International, Radnor, PA) and 1 M DTT
(Fisher Scientific, Pittsburgh, PA) was used to passively lyse adhered cells. The lysate was
collected and flash frozen before clarification by centrifugation. Protein concentration was
calculated using the Pierce® Microplate BCA Protein Assay Kit – Reducing Agent Compatible
(ThermoScientific, Waltham, MA) and run on an Any kDTM
Mini-Protean TGXTM
precast gel
(Bio-Rad; Hercules, CA). Transfer was conducted using Bio-Rad Midi Transfer Packs on the
Bio-Rad Trans-Blot® Turbo Blotting System. The membranes were blocked in 5% non-fat dry
milk (Sigma-Aldrich, St. Louis, MO) in TBST and probed with 1:800 anti-ABHD5 antibody
(Abnova, Cat# H00051099-M01, Taiwan) in 4% BSA (Applied Biosystems, Cat# AM2616) in
TBST. Goat anti-rabbit secondary antibody (Abcam, Cat# ab131366) was diluted 1:3,000 in 1%
milk/TBST. β-actin peroxidase (Sigma-Aldrich, St. Louis, MO, Cat# A3854) or GAPDH (Cell
Signaling; Danvers, MA, Cat# 8884s) diluted 1:40,000 in 1% milk/TBST were used as controls.
Signal was detected using the Amersham™ ECL™ Prime Western Blotting Detection Reagent
(GE Healthcare Life Sciences; Piscataway, NJ) following manufacturer instructions and exposed
using the LiCor C-DiGit Blot scanner (LiCor, Lincoln, NE). Signal intensity was determined by
densitometry using LiCor Biosciences Image Studio Software.
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Reporter gene (Luciferase) assays
Human embryonic kidney 293T (HEK293T) cells were plated at 1x105 cells/mL for 24
hours prior to transient transfection using DharmaFect 4 and 500 ng/mL MT01 Firefly/Renilla
luciferase reporter with the entire 3’ UTR of HMGCS2 cloned immediately downstream of
Firefly luciferase (Genecopoeia). Cells were dual transfected with 10 nM of miR-29a mimic for
48 hours prior to cell lysis and dual luciferase assays (Genecopoeia). Site-directed mutagenesis
was completed using QuickChange II XL kits (Stratagene) and the following primers – Reverse
5'-agccgttgcaccgtcaggcacaggg-3' and Forward 5'-ccctgtgcctgacggtgcaacggct-3'. A 3 base deletion
was created in the middle of the predicted “seed” target site for miR-29
(…tgcctgacggtggtgcaacggctgatgga…).
Bioinformatics
ChIP-seq data for Foxa2 in mouse liver and islet were published previously(30).
Chromatin occupancy sites based on these ChIP-seq data were obtained directly from the lead
author of the study (Brad Hoffman, University of British Columbia). Candidate Foxa2 target
genes in mouse liver and islet were assembled by cross-referencing the chromosomal locations
of Foxa2 occupancy sites with gene promoter regions (defined as windows 5 kb upstream of
transcription start sites as annotated in the RefSeq database). The miR-29ab promoter region was
identified as recently described(31). Target site prediction for miR-29 was performed with
TargetScan 6.2 (downloaded from http://targetscan.org). Statistical enrichment of predicted miR-
29 target sites among Foxa2 target genes in the mouse liver and islet was assessed according to
our recently published method, mirHub(27), using the “non-network” mode and requiring a
predicted target site to be conserved among at least three mammalian species including mouse.
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Results
Hepatic miR-29 is up-regulated in animal models of insulin resistance and is corrected by
treatment with the insulin-sensitizing drug Pioglitazone
To determine if hepatic miR-29 levels are altered in the insulin resistant state, we
investigated two different animal models of metabolic dysfunction. First, we studied female
C57BL/6J mice placed on a 16-week high-fat diet (HFD; 45% kcal from fat), which resulted in
significantly elevated (~1.8-fold, P < 0.001) fasting blood glucose levels relative to age-, gender-
, and strain-matched mice on low-fat diet (LFD; 10% kcal from fat) (Figure 1A). We performed
deep sequencing of liver small RNAs and found that miR-29b (~1.8-fold, P < 0.05) and miR-29c
(~1.9-fold, P < 0.001) were significantly elevated in HFD-fed mice (Figure 1B-C,
Supplementary Table 1), matching the fold increase in miR-802 (Figure 1B, Supplementary
Table 1), which was previously identified as a critical mediator of obesity-induced glucose
intolerance(20). To validate this finding, we performed real time quantitative PCR (RT-qPCR)
and confirmed that hepatic levels of miR-29 were significantly increased in HFD-fed mice
(Figure 1D).
Next, we examined the Zucker Diabetic Fatty (ZDF) fa/fa rat model, which closely
mimics human adult onset diabetes(32). We showed that, as expected, fasting blood glucose
levels were significantly elevated (~2.5-fold, P < 0.005) in 12-week old male obese fa/fa rats
compared to age- and gender-matched lean healthy littermates (Figure 2A). We then
demonstrated by RT-qPCR that hepatic miR-29a and miR-29c levels were significantly (P <
0.05) higher for the fa/fa rats compared to the lean littermate controls (Figure 2B). Strikingly, we
also observed that treatment with the insulin-sensitizing drug Pioglitazone for four weeks, which
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markedly improved glycemia (Figure 2A), reduced hepatic miR-29 expression to levels
comparable to that of the lean controls (Figure 2B).
Hepatic miR-29 expression is controlled in part by the insulin-regulated transcription factor
FOXA2
To investigate the molecular mechanism(s) that mediate the up-regulation of miR-29 in
insulin resistance, we sought to identify hepatic transcription factors (TFs) regulated by insulin
signaling that could be involved in the control of miR-29 expression. First, we identified the
transcription start sites (TSS) of miR-29a/b-1 (chromosome 7) and miR-29b-2/c (chromosome 1)
in human hepatoma cells (HepG2) by analyzing chromatin data from ENCODE using our
previously described bioinformatic pipeline(31). This strategy revealed that the most proximal
active TSS for miR-29a/b-1 is ~36.5 kb upstream of the mature miR-29a sequence and for miR-
29b-2/c is ~20kb upstream of the mature miR-29c sequence. We scanned these regions for areas
of open chromatin and TF occupancy in HepG2 cells, as determined by ENCODE, and found
>10 binding sites for FOXA2 at the miR-29a/b-1 locus and 4 binding sites at the miR-29b-2/c
locus (Figure 3A). FOXA2 is negatively regulated by insulin(33; 34), and opposes insulin
action(35) by promoting hepatic lipid catabolism and fatty acid oxidation(36). To further support
the finding in HepG2 cells, we mined a recently published TF ChIP-seq dataset from adult
mouse liver(30) and detected Foxa2 chromatin occupancy at the mouse miR-29 promoter regions
(data not shown).
We next performed real time quantitative PCR and observed that hepatic Foxa2 mRNA
levels were increased in both HFD-fed mice (Figure 3B) and diabetic fa/fa rats (P < 0.05; Figure
3C). Moreover, as with miR-29 (Figure 3D), hepatic Foxa2 expression in the fa/fa rats returned
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to that of the lean controls upon treatment with Pioglitazone (Figure 3C). To more directly
evaluate the potential for FOXA2 to regulate hepatic miR-29 levels, we performed siRNA-
mediated knockdown of FOXA2 in Huh7 cells. After 48 hours of siRNA treatment, FOXA2
mRNA was significantly reduced (P < 10-12
, Figure 3D). Under these conditions, we observed an
almost 2-fold down-regulation of miR-29a (P < 0.001), miR-29b (P < 0.05), and miR-29c (P <
0.01) (Figure 3D). We also transiently transfected Huh7 cells with a FOXA2 expression vector
(1 ug), which led to a ~172-fold up-regulation in FOXA2 mRNA levels (P < 0.05), and a
concomitant >2-fold increase in miR-29a (P < 0.05), miR-29b (P = 0.06), and miR-29c (P <
0.05). Collectively, these data suggest that the insulin-regulated FOXA2 is a transcriptional
activator of miR-29.
miR-29 fine-tunes FOXA2 mediated regulation of key hepatic lipid metabolism genes
Recent studies of gene regulatory networks (GRNs) indicate that coordinated regulation
by TFs and miRNAs confer robustness against environmental fluctuation(37). We assessed the
extent to which miR-29 is predicted to regulate Foxa2 gene targets in the liver. First, we
assembled a list of high-confidence hepatic target genes for Foxa2 from a published ChIP-seq
study in mouse liver (Methods). We then determined, using our previously published method
mirHub(27), that the Foxa2 mouse liver target gene set was significantly enriched for predicted
miR-29 target sites (Figure 4A). Notably, we did not observe this enrichment among Foxa2
target genes in the mouse pancreatic islet, in which the Foxa2 regulatory network is re-wired
relative to the liver(30) (Figure 4A). To evaluate further the predicted FOXA2-miR-29 feed-
forward circuit, we experimentally tested three specific instances of the circuit with the genes
HMGCS2, ABHD5, and PPARGC1A, which encode proteins that activate the enzymatic
breakdown of fat in the liver(38; 39). The mRNA levels of all three genes in Huh7 cells were
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significantly (P < 0.01) increased by the miR-29a locked nucleic acid (LNA) inhibitor and
significantly (P < 0.05) reduced by the miR-29a mimic (Figure 4B). Consistent with this
observation, the protein levels of ABHD5 were also significantly (P < 0.05) up-regulated by the
miR-29a LNA inhibitor after 48 hours (Figure 4C). Also, to determine whether miR-29
regulation of HMGCS2 is mediated through the 3’ UTR, we performed a reporter gene assay
(Methods). Over-expression of the miR-29a mimic (100 nM) in HEK293T cells significantly
reduced (P < 0.01, ~65% loss) relative Firefly luciferase activity when the HMGCS2 3’ UTR was
inserted downstream of the Firefly reporter gene (Figure 4D). Moreover, targeted deletion (3 bp)
of the predicted miR-29 target site in the HMGCS2 3’ UTR substantially mitigated the repressive
effect of miR-29 on Firefly activity (Figure 4D). Finally, siRNA-mediated knockdown of
FOXA2 led to a significant (P < 0.01) decrease in the expression of HMGCS2, ABHD5, and
PPARGC1A (Figure 4E). The latter observation suggests that FOXA2 is the primary driver of
the expression levels of its target genes, whereas miR-29 serves as a feed-forward negative
modulator (Figure 5).
Discussion
This study leveraged in vivo, in vitro, and in silico analyses to uncover a role for miR-29
as a potentially critical regulator of hepatic metabolic pathways. A prior study suggested that
miR-29 is significantly elevated in the livers of the diabetic mouse model db/db(40); however, to
our knowledge this result had not been validated in other models. We showed in this study that
liver miR-29 levels are elevated in two different animal models of metabolic dysfunction, and
notably, are returned to normal levels upon treatment with an insulin sensitizer, Pioglitazone, in
the ZDF diabetic rat. This finding signals the possibility that miRNAs could serve as tissue
biomarkers of drug efficacy in type 2 diabetes.
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Two recent miRNA profiling studies reported that type 2 diabetes might be associated
with reduced levels of plasma miR-29(41; 42). We observe in this study that miR-29 is elevated
in the liver of animals with insulin resistance and diabetes. The apparent inverse correlation
between plasma and liver miR-29 levels in type 2 diabetes is intriguing. It is now widely
appreciated that miRNAs are stably present in circulation and are transported by a variety of
different types of extracellular vehicles (EVs), including exosomes and high-density
lipoproteins(43-47). Several studies have shown that numerous cell types secrete miRNAs,
which can then be loaded onto EVs and delivered to recipient cells with functional integrity(48-
50). However, the mechanisms that regulate intercellular miRNA transfer remain poorly
characterized and it represents a nascent but promising topic of research. Progress in this area
will be critical for understanding why liver miR-29 is elevated but plasma miR-29 is reduced in
type 2 diabetes. miR-29 is highly expressed in numerous metabolic tissues, including the
pancreatic islet(27; 51), and the relative contribution of each of these tissues to circulating miR-
29 remains to be determined and merits further investigation.
We also demonstrated in this study that hepatic miR-29 expression is likely controlled at
least in part by the insulin-regulated transcription factor, FOXA2, which contains >10 ChIP-seq
derived binding sites in human hepatoma cells at the miR-29ab genomic locus on chromosome 7
and 4 binding sites at the miR-29bc genomic locus on chromosome 1. The evaluation of the
combinatorial effect of these binding sites on miR-29 transcription is not trivial; however, it
certainly warrants further investigation in order to more definitively establish direct FOXA2-
mediated regulation of miR-29. Moreover, future studies in vivo should establish the extent to
which FOXA2 controls miR-29 during hepatic insulin resistance.
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Finally, we showed that miR-29 serves as a dampener of FOXA2-mediated activation of
key lipid metabolism genes. For example, FOXA2 transcriptionally activates HMGCS2, which in
turn is directly repressed by miR-29. It has been postulated that such TF:miRNA regulatory
circuits, termed incoherent feed-forward loops, are likely important for noise buffering of gene
expression(37; 52; 53). Further detailed studies in vivo may help elucidate the physiological
importance of the FOXA2:miR-29 regulatory circuit in lipid homeostasis.
Overall, this study strongly suggests that miR-29 merits further investigation as a
candidate biomarker of metabolic status and drug efficacy, an etiological factor in type 2
diabetes, and a potentially important therapeutic target for a range of metabolic disorders.
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Acknowledgements
Praveen Sethupathy is the guarantor of this work and, as such, had full access to all of
the data in the study and takes responsibility for the integrity of the data and the accuracy of the
data analysis. C.L.K. researched data and edited the manuscript. B.C.E.P. researched data and
edited the manuscript. E.E.F. researched data. C.B. researched data. S.D. researched data. V.T.
researched data. S.B. researched data. S.T. researched data. P.K.L. contributed to discussion.
K.C.V. researched data and contributed to the discussion. P.S. researched data, contributed to
discussion, and wrote the manuscript.
The authors would like to thank Michael Erdos of NIH, Samir Kelada and Jeanette
Baran-Gale of UNC Chapel Hill, and Jonathan Haldeman of Duke University for their helpful
suggestions regarding the study and the manuscript, Stanley Lemon of UNC Chapel Hill for
generously sharing Huh7 cells, and Brad Hoffman of the University of British Columbia for
sharing with us the chromatin occupancy sites for FOXA2 in mouse liver and islet based on a
previously published study. This work was supported in part by an R00 grant (DK091318-02)
from NIDDK/NIH (awarded to P.S.), a Pilot & Feasibility grant (NIDDK/NIH P30DK056350)
from the UNC Nutrition Obesity Research Center (awarded to P.S.), a UNC Genetics and
Molecular Biology T32 training grant (GM007092-39) from NIGMS/NIH and UNC IMSD
Fellowship through the Education Program grant (R25GM055336-13) from NIGMS/NIH
(awarded to B.C.E.P.), an R01 grant (RHL109650) from NHLBI/NIH (awarded to S.B.B.), a K99
grant (DK100539) from NIDDK/NIH (awarded to J.M.) a K22 grant (K22HL113039) from
NHLBI/NIH (awarded to K.C.V.), and a grant from the German Federal Ministry of Education
and Research awarded to the German Center for Diabetes Research (P.E.S.). We confirm that no
conflict of interest exists for any of the authors.
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Figure Legends
Figure 1. Hepatic miR-29 levels are up-regulated in diet-induced insulin resistance in mice.
(A) Fasting blood glucose levels of C57BL/6J female mice on high-fat diet (HFD 16 weeks;
n=3) and matched low-fat diet (LFD 16 weeks; n=3) are shown. (B) miRNA expression levels
(RPMM, reads per million mapped reads) based on deep sequencing analysis of small RNAs
from the livers of HFD-fed (n=2) and LFD-fed (n=2) C57BL/6J female mice are shown. Each
circle represents a miRNA that is expressed at RPMM > 100 in at least one murine liver sample.
Dashed blue lines represent 1.5-fold difference in expression between HFD-fed and LFD-fed
mice. (C) Relative levels (based on sequencing) of miR-29a, miR-29b, and miR-29c in the livers
of HFD-fed (n=2) and LFD-fed (n=2) C57BL/6J female mice are shown. (D) Relative levels
(based on RT-qPCR) of miR-29a, miR-29b, and miR-29c in the livers of HFD-fed (n=3) and
LFD-fed (n=3) C57BL/6J female mice are shown. P-values were calculated according to the one-
tailed unpaired Student’s t-test. *, P < 0.05; **, P < 0.01; ***, P < 0.001.
Figure 2. Hepatic miR-29 levels are elevated in a rat model of diabetes and corrected by
treatment with the insulin-sensitizing drug Pioglitazone. (A & B) Fasting blood glucose
levels (A) and relative hepatic levels (based on RT-qPCR) of miR-29a, miR-29b, and miR-29c
(B) in 12-week old healthy male rats (n=8), Zucker Diabetic Fatty (ZDF) fa/fa male littermates
(n=11), and Pioglitazone-treated (4 weeks) ZDF fa/fa male rats (n=6) are shown. P-values were
calculated according to the one-tailed unpaired Student’s t-test. *, P < 0.05; **, P < 0.01; ***, P
< 0.001.
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Figure 3. FOXA2 regulates miR-29 expression. (A) FOXA2 occupancy in human hepatoma
cells (HepG2) at the miR-29ab and mir-29b-2/c genomic loci are shown (based on ENCODE
ChIP-seq data). LOC646329 represents the putative primary transcript of miR-29a and miR-29b-
1 on chromosome 7 and Pri-mir-29b-2 represents the putative primary transcript of miR-29b-2
and miR-29c on chromosome 1. (B) Relative levels of Foxa2 mRNA in the livers of C57BL/6J
female mice on high-fat diet (HFD 16 weeks; n=3) and matched low-fat diet (LFD 16 weeks;
n=3) are shown. (C) Relative levels of Foxa2 mRNA in the livers of 16-week old healthy male
rats (n=8), Zucker Diabetic Fatty (ZDF) fa/fa male littermates (n=11), and Pioglitazone-treated
(4 weeks) ZDF fa/fa male rats (n=6) are shown. (D) Effects of FOXA2-siRNA treatment (100
nM) in Huh7 cells on FOXA2 (mock, n=14; siRNA, n=13), miR-29a (mock, n=12; siRNA,
n=12), miR-29b and miR-29c (mock, n=10; siRNA, n=8) expression levels are shown. (E)
Effects of FOXA2 over-expression plasmid (1 ug) in Huh7 cells on FOXA2 (mock, n=6;
plasmid, n=5), miR-29a (mock, n=6; plasmid, n=5), miR-29b (mock, n=5; plasmid, n=4), and
miR-29c (mock, n=6; plasmid, n=5) are shown. All transfections were conducted in triplicate
and results were validated by at least two independent experiments. P-values were calculated
according to the two-tailed unpaired Student’s t-test. *, P < 0.05; **, P < 0.01. ***, P < 0.001.
Figure 4. miR-29 fine-tunes FOXA2-mediated regulation of key lipid metabolism genes. (A)
Significant enrichment of predicted miR-29 target sites among FOXA2 bound genes in mouse
liver but not in mouse islet is shown. (B) Effects of the miR-29a mimic (10 nM) and the miR-29a
locked nucleic acid inhibitor (LNA, 10 nM) in Huh7 cells on the mRNA levels of FOXA2-bound
genes HMGCS2 (mimic, n=7; LNA, n=7), ABHD5 (mimic, n=8; LNA, n=6), and PPARGC1A
(mimic, n=7; LNA, n=7) are shown. (C) Effect of the miR-29a inhibitor (LNA, 10 nM) in Huh7
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cells on protein levels of ABHD5 is shown (mock, n=3; LNA, n=3). (D) Effects of the miR-29a
mimic (100nM) in HEK293T cells on the relative activity of Firefly reporter constructs
containing either wild-type or mutated HMGCS2 3’ UTR are shown. Firefly activity was
normalized to Renilla activity. (E) Effects of FOXA2-siRNA treatment (100 nM) in Huh7 cells
on mRNA levels of HMGCS2 (mock, n=10; siRNA, n=9), ABHD5 (mock, n=10; siRNA, n=10),
and PPARGC1A (mock, n=8; siRNA, n=4) are shown. P-values were calculated according to the
two-tailed unpaired Student’s t-test. *, P < 0.05; **, P < 0.01; ***, P < 0.001.
Figure 5. Schematic of the FOXA2:miR-29 regulatory circuit in the liver. A possible model
of FOXA2:miR-29 circuitry in the liver is shown. In the insulin resistant state, FOXA2 activity is
up-regulated, which in turn elevates miR-29 levels. FOXA2 drives the expression of genes
involved in lipid metabolism and miR-29 acts as a feed-forward fine-tuner of many of the same
genes.
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Figure 1. Hepatic miR-29 levels are up-regulated in diet-induced insulin resistance in mice. (A) Fasting blood glucose levels of C57BL/6J female mice on high-fat diet (HFD 16 weeks; n=3) and matched low-fat diet (LFD 16 weeks; n=3) are shown. (B) miRNA expression levels (RPMM, reads per million mapped reads) based on
deep sequencing analysis of small RNAs from the livers of HFD-fed (n=2) and LFD-fed (n=2) C57BL/6J female mice are shown. Each circle represents a miRNA that is expressed at RPMM > 100 in at least one murine liver sample. Dashed blue lines represent 1.5-fold difference in expression between HFD-fed and
LFD-fed mice. (C) Relative levels (based on sequencing) of miR-29a, miR-29b, and miR-29c in the livers of HFD-fed (n=2) and LFD-fed (n=2) C57BL/6J female mice are shown. (D) Relative levels (based on RT-qPCR) of miR-29a, miR-29b, and miR-29c in the livers of HFD-fed (n=3) and LFD-fed (n=3) C57BL/6J female mice are shown. P-values were calculated according to the one-tailed unpaired Student’s t-test. *, P < 0.05; **,
P < 0.01; ***, P < 0.001. 109x261mm (72 x 72 DPI)
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Figure 2. Hepatic miR-29 levels are elevated in a rat model of diabetes and corrected by treatment with the insulin-sensitizing drug Pioglitazone. (A & B) Fasting blood glucose levels (A) and relative hepatic levels
(based on RT-qPCR) of miR-29a, miR-29b, and miR-29c (B) in 12-week old healthy male rats (n=8), Zucker
Diabetic Fatty (ZDF) fa/fa male littermates (n=11), and Pioglitazone-treated (4 weeks) ZDF fa/fa male rats (n=6) are shown. P-values were calculated according to the one-tailed unpaired Student’s t-test. *, P <
0.05; **, P < 0.01; ***, P < 0.001. 187x70mm (72 x 72 DPI)
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Figure 3. FOXA2 regulates miR-29 expression. (A) FOXA2 occupancy in human hepatoma cells (HepG2) at the miR-29ab and mir-29b-2/c genomic loci are shown (based on ENCODE ChIP-seq data). LOC646329
represents the putative primary transcript of miR-29a and miR-29b-1 on chromosome 7 and Pri-mir-29b-2
represents the putative primary transcript of miR-29b-2 and miR-29c on chromosome 1. (B) Relative levels of Foxa2 mRNA in the livers of C57BL/6J female mice on high-fat diet (HFD 16 weeks; n=3) and matched low-fat diet (LFD 16 weeks; n=3) are shown. (C) Relative levels of Foxa2 mRNA in the livers of 16-week old healthy male rats (n=8), Zucker Diabetic Fatty (ZDF) fa/fa male littermates (n=11), and Pioglitazone-
treated (4 weeks) ZDF fa/fa male rats (n=6) are shown. (D) Effects of FOXA2-siRNA treatment (100 nM) in Huh7 cells on FOXA2 (mock, n=14; siRNA, n=13), miR-29a (mock, n=12; siRNA, n=12), miR-29b and miR-29c (mock, n=10; siRNA, n=8) expression levels are shown. (E) Effects of FOXA2 over-expression plasmid (1 ug) in Huh7 cells on FOXA2 (mock, n=6; plasmid, n=5), miR-29a (mock, n=6; plasmid, n=5), miR-29b (mock, n=5; plasmid, n=4), and miR-29c (mock, n=6; plasmid, n=5) are shown. All transfections were conducted in triplicate and results were validated by at least two independent experiments. P-values were
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calculated according to the two-tailed unpaired Student’s t-test. *, P < 0.05; **, P < 0.01. ***, P < 0.001. 138x245mm (72 x 72 DPI)
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Figure 4. miR-29 fine-tunes FOXA2-mediated regulation of key lipid metabolism genes. (A) Significant enrichment of predicted miR-29 target sites among FOXA2 bound genes in mouse liver but not in mouse
islet is shown. (B) Effects of the miR-29a mimic (10 nM) and the miR-29a locked nucleic acid inhibitor (LNA, 10 nM) in Huh7 cells on the mRNA levels of FOXA2-bound genes HMGCS2 (mimic, n=7; LNA, n=7), ABHD5 (mimic, n=8; LNA, n=6), and PPARGC1A (mimic, n=7; LNA, n=7) are shown. (C) Effect of the miR-29a inhibitor (LNA, 10 nM) in Huh7 cells on protein levels of ABHD5 is shown (mock, n=3; LNA, n=3). (D)
Effects of the miR-29a mimic (100nM) in HEK293T cells on the relative activity of Firefly reporter constructs containing either wild-type or mutated HMGCS2 3’ UTR are shown. Firefly activity was normalized to Renilla
activity. (E) Effects of FOXA2-siRNA treatment (100 nM) in Huh7 cells on mRNA levels of HMGCS2 (mock, n=10; siRNA, n=9), ABHD5 (mock, n=10; siRNA, n=10), and PPARGC1A (mock, n=8; siRNA, n=4) are
shown. P-values were calculated according to the two-tailed unpaired Student’s t-test. *, P < 0.05; **, P < 0.01; ***, P < 0.001.
212x206mm (72 x 72 DPI)
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Figure 5. Schematic of the FOXA2:miR-29 regulatory circuit in the liver. A possible model of FOXA2:miR-29 circuitry in the liver is shown. In the insulin resistant state, FOXA2 activity is up-regulated, which in turn
elevates miR-29 levels. FOXA2 drives the expression of genes involved in lipid metabolism and miR-29 acts as a feed-forward fine-tuner of many of the same genes.
212x75mm (72 x 72 DPI)
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miRNA HFD1 HFD2 Mean.HFD StDev LFD1 LFD2 Mean.LFD StDev2Ratio
HFD/LFD
mmu-mir-22-3p 98707.6 79959.1 89333.4 13257.2 49740.7 68103.6 58922.1 12984.5 1.5161
mmu-mir-192-5p 98494.1 78245.3 88369.7 14318.0 36784.5 33486.6 35135.6 2332.0 2.5151
mmu-mir-92a-1-3p 20202.7 18798.3 19500.5 993.0 21169.4 30198.4 25683.9 6384.4 0.7592
mmu-mir-122-5p 31218.5 26676.9 28947.7 3211.4 23830.0 29978.6 26904.3 4347.7 1.0760
mmu-mir-192-5p_+_1 45562.2 29238.6 37400.4 11542.5 16081.3 22648.1 19364.7 4643.4 1.9314
mmu-mir-148a-3p 33983.2 25526.2 29754.7 5980.0 14366.1 21358.3 17862.2 4944.2 1.6658
mmu-mir-143-3p 12533.9 8682.9 10608.4 2723.1 5750.7 20866.3 13308.5 10688.4 0.7971
mmu-mir-26a-2-5p 15432.3 10265.7 12849.0 3653.3 7328.9 13989.2 10659.0 4709.6 1.2055
mmu-mir-26a-1-5p 15397.4 10239.2 12818.3 3647.4 7309.7 13949.0 10629.3 4694.7 1.2059
mmu-mir-30a-5p 18849.1 16457.8 17653.4 1690.9 9319.1 13488.6 11403.8 2948.3 1.5480
mmu-mir-27b-3p 17357.4 7546.6 12452.0 6937.3 3974.1 12986.5 8480.3 6372.7 1.4683
mmu-mir-191-5p 8942.0 6861.9 7902.0 1470.8 5615.1 12637.5 9126.3 4965.6 0.8658
mmu-mir-10a-5p 12949.5 9192.2 11070.9 2656.8 5841.3 12434.1 9137.7 4661.8 1.2116
mmu-mir-99b-5p 3130.8 2251.9 2691.4 621.5 3187.0 10904.4 7045.7 5457.0 0.3820
mmu-mir-125a-5p 3697.9 2802.7 3250.3 632.9 3577.2 10828.5 7202.9 5127.4 0.4513
mmu-mir-21-5p 7502.2 6559.6 7030.9 666.5 3195.5 9347.7 6271.6 4350.3 1.1211
mmu-let-7f-2-5p 9000.4 6036.4 7518.4 2095.9 3745.2 8205.9 5975.5 3154.2 1.2582
mmu-mir-378-3p 6920.8 7175.9 7048.3 180.3 4883.2 7628.6 6255.9 1941.3 1.1267
mmu-mir-30d-5p 6215.8 5671.9 5943.9 384.6 4603.3 7301.6 5952.5 1908.0 0.9986
mmu-let-7f-1-5p 7679.4 5136.7 6408.1 1798.0 3171.0 6864.3 5017.7 2611.6 1.2771
mmu-mir-151-3p 3705.4 3421.0 3563.2 201.1 3522.5 6177.2 4849.9 1877.2 0.7347
mmu-mir-486-5p 9606.2 23077.0 16341.6 9525.3 13429.5 5934.8 9682.2 5299.6 1.6878
mmu-mir-3107-5p 9579.5 23005.5 16292.5 9493.6 13388.7 5920.0 9654.4 5281.2 1.6876
mmu-mir-10a-5p_+_1 5217.3 3677.0 4447.1 1089.2 2685.4 5860.0 4272.7 2244.8 1.0408
mmu-let-7a-1-5p 4262.1 3573.0 3917.5 487.3 3162.3 5490.7 4326.5 1646.4 0.9055
mmu-let-7a-2-5p 4241.5 3542.8 3892.2 494.0 3127.3 5414.7 4271.0 1617.4 0.9113
mmu-mir-126-5p 10331.4 6151.2 8241.3 2955.8 3706.1 4980.7 4343.4 901.2 1.8974
mmu-let-7c-2-5p 3419.5 3462.4 3440.9 30.4 3691.6 4768.4 4230.0 761.4 0.8135
mmu-let-7c-1-5p 3189.4 3246.6 3218.0 40.5 3436.9 4480.4 3958.7 737.8 0.8129
mmu-mir-181a-1-5p 1608.5 1713.8 1661.1 74.5 1872.0 4300.0 3086.0 1716.9 0.5383
mmu-mir-181a-2-5p 1608.2 1713.8 1661.0 74.7 1871.8 4299.9 3085.9 1716.9 0.5383
mmu-mir-26b-5p 5801.4 3556.4 4678.9 1587.4 2460.4 4277.2 3368.8 1284.7 1.3889
mmu-let-7g-5p 5134.9 3324.5 4229.7 1280.1 2404.2 4195.4 3299.8 1266.6 1.2818
mmu-mir-100-5p 1617.9 1174.4 1396.2 313.6 1274.3 4103.4 2688.8 2000.4 0.5192
mmu-mir-16-1-5p 5071.7 4262.2 4666.9 572.4 2192.7 3260.4 2726.5 755.0 1.7117
mmu-mir-16-2-5p 5048.7 4243.9 4646.3 569.0 2174.5 3244.6 2709.5 756.7 1.7148
mmu-mir-151-5p 2143.7 1941.1 2042.4 143.2 1478.8 2959.6 2219.2 1047.1 0.9203
mmu-let-7b-5p 2307.8 2275.6 2291.7 22.8 2746.5 2950.6 2848.6 144.3 0.8045
mmu-mir-30e-5p 3027.0 2946.0 2986.5 57.3 1469.4 2160.4 1814.9 488.6 1.6455
mmu-let-7i-5p 959.2 1013.6 986.4 38.4 719.4 2102.5 1411.0 978.0 0.6991
Page 30 of 55
For Peer Review Only
Diabetes
mmu-mir-125b-1-5p 861.1 704.5 782.8 110.7 781.7 1982.5 1382.1 849.1 0.5664
mmu-mir-125b-2-5p 829.9 679.4 754.7 106.4 751.5 1912.2 1331.8 820.8 0.5666
mmu-let-7d-5p 1521.1 1293.7 1407.4 160.8 968.0 1908.6 1438.3 665.0 0.9785
mmu-mir-29a-3p 1629.1 1542.4 1585.8 61.3 1044.2 1890.8 1467.5 598.7 1.0806
mmu-mir-194-2-5p 2804.2 2045.9 2425.1 536.2 1130.9 1250.8 1190.8 84.8 2.0364
mmu-mir-126-3p 1410.7 1072.2 1241.5 239.4 662.2 1233.3 947.8 403.8 1.3099
mmu-mir-130a-3p 1133.8 966.7 1050.3 118.2 710.6 1126.5 918.5 294.1 1.1434
mmu-mir-30c-2-5p 1653.2 1461.1 1557.2 135.9 747.1 1112.8 929.9 258.6 1.6745
mmu-mir-30c-1-5p 1653.1 1461.0 1557.0 135.8 747.1 1112.6 929.9 258.4 1.6745
mmu-mir-182-5p 647.2 714.1 680.7 47.3 696.4 1108.8 902.6 291.6 0.7541
mmu-mir-423-3p 749.0 822.2 785.6 51.7 753.7 1102.3 928.0 246.5 0.8466
mmu-mir-25-3p 805.6 860.6 833.1 38.9 534.5 1081.6 808.1 386.9 1.0309
mmu-mir-92a-2-3p 631.1 662.9 647.0 22.5 652.8 1038.6 845.7 272.9 0.7651
mmu-mir-351-5p 651.7 658.5 655.1 4.8 635.3 1030.1 832.7 279.2 0.7867
mmu-mir-194-1-5p 2404.8 1608.0 2006.4 563.4 935.6 1010.0 972.8 52.6 2.0626
mmu-mir-142-5p_-_2 616.8 649.8 633.3 23.4 224.1 967.2 595.6 525.4 1.0633
mmu-mir-93-5p 595.4 588.6 592.0 4.8 383.4 924.2 653.8 382.3 0.9055
mmu-let-7d-3p 605.3 570.7 588.0 24.5 618.6 880.1 749.4 184.9 0.7846
mmu-mir-146a-5p 575.9 475.7 525.8 70.9 291.1 865.9 578.5 406.4 0.9089
mmu-mir-5115_-_1 429.2 1403.8 916.5 689.2 1597.8 767.2 1182.5 587.3 0.7750
mmu-mir-101b-3p 1739.9 1602.9 1671.4 96.8 731.2 765.2 748.2 24.0 2.2338
mmu-mir-5099_-_2 321.6 334.6 328.1 9.2 396.9 732.9 564.9 237.6 0.5808
mmu-mir-423-5p 620.4 466.2 543.3 109.0 381.8 727.1 554.5 244.2 0.9798
mmu-mir-99a-5p 508.2 379.8 444.0 90.8 329.0 724.2 526.6 279.4 0.8431
mmu-mir-31-5p 266.0 294.8 280.4 20.4 196.2 662.3 429.3 329.6 0.6532
mmu-mir-23b-3p 783.1 584.3 683.7 140.6 406.1 640.8 523.4 166.0 1.3063
mmu-mir-484 222.3 288.0 255.1 46.5 254.0 628.5 441.3 264.9 0.5782
mmu-mir-5115_-_6 293.2 1037.9 665.5 526.6 930.7 596.9 763.8 236.0 0.8713
mmu-mir-126-3p_+_1 722.0 573.0 647.5 105.4 338.9 593.4 466.2 180.0 1.3890
mmu-let-7e-5p 168.4 150.9 159.7 12.4 205.3 589.8 397.6 271.9 0.4016
mmu-mir-148b-3p 612.5 466.5 539.5 103.2 300.5 576.2 438.4 194.9 1.2308
mmu-mir-501-3p 213.1 189.3 201.2 16.8 206.1 558.9 382.5 249.5 0.5259
mmu-mir-199a-2-3p 150.5 100.6 125.6 35.3 88.6 555.6 322.1 330.2 0.3898
mmu-mir-27a-3p 274.8 147.5 211.2 90.0 73.2 546.6 309.9 334.7 0.6814
mmu-mir-199b-3p 147.0 98.6 122.8 34.2 86.6 544.6 315.6 323.9 0.3891
mmu-mir-199a-1-3p 147.0 98.6 122.8 34.2 86.6 544.6 315.6 323.9 0.3891
mmu-mir-744-5p 412.9 377.3 395.1 25.2 407.9 530.9 469.4 87.0 0.8418
mmu-mir-125b-1-5p_+_1 217.2 168.4 192.8 34.5 207.1 504.1 355.6 210.0 0.5422
mmu-mir-140-3p_+_1 345.9 372.1 359.0 18.6 242.5 492.5 367.5 176.8 0.9768
mmu-mir-125b-2-5p_+_1 216.0 166.8 191.4 34.7 205.0 489.7 347.4 201.3 0.5510
mmu-mir-127-3p 87.7 84.8 86.3 2.1 87.7 474.1 280.9 273.2 0.3071
Page 31 of 55
For Peer Review Only
Diabetes
mmu-mir-5115 308.6 923.2 615.9 434.6 2581.4 473.0 1527.2 1490.9 0.4033
mmu-mir-101b-3p_-_1 997.5 836.8 917.2 113.6 354.0 465.8 409.9 79.0 2.2375
mmu-mir-107-3p 775.9 604.9 690.4 120.9 397.8 459.9 428.8 43.9 1.6099
mmu-mir-103-2-3p 466.7 410.0 438.4 40.1 266.3 450.1 358.2 130.0 1.2238
mmu-mir-200b-3p 161.9 89.6 125.8 51.1 87.0 449.6 268.3 256.4 0.4687
mmu-mir-150-5p 90.3 128.6 109.5 27.0 120.6 442.3 281.4 227.5 0.3889
mmu-mir-103-1-3p 454.5 402.1 428.3 37.1 259.0 434.3 346.6 124.0 1.2356
mmu-mir-221-3p 300.8 282.5 291.6 13.0 225.7 411.1 318.4 131.1 0.9160
mmu-mir-23a-3p 243.7 170.1 206.9 52.0 127.8 408.5 268.2 198.5 0.7717
mmu-mir-186-5p 465.1 440.8 453.0 17.2 221.7 392.2 306.9 120.6 1.4758
mmu-mir-101a-3p 616.6 711.5 664.1 67.1 337.1 368.2 352.6 22.0 1.8832
mmu-mir-191-5p_+_1 227.1 183.5 205.3 30.8 150.4 364.9 257.7 151.6 0.7967
mmu-mir-30b-5p 478.6 476.0 477.3 1.8 219.5 359.5 289.5 99.0 1.6488
mmu-mir-5115_-_2 189.8 624.3 407.1 307.2 372.2 346.0 359.1 18.5 1.1335
mmu-mir-28-5p 281.2 268.3 274.8 9.1 205.4 337.7 271.6 93.5 1.0119
mmu-mir-320-3p 228.0 234.6 231.3 4.7 273.5 336.9 305.2 44.8 0.7579
mmu-mir-24-1-3p 272.1 228.8 250.5 30.6 142.5 323.2 232.9 127.8 1.0756
mmu-mir-24-2-3p 272.1 228.8 250.5 30.6 142.5 323.2 232.9 127.8 1.0756
mmu-mir-5105_+_8 442.5 400.4 421.5 29.8 297.8 322.8 310.3 17.7 1.3584
mmu-mir-140-3p 199.1 205.0 202.0 4.2 128.3 312.5 220.4 130.3 0.9165
mmu-mir-101a-3p_-_1 454.6 437.7 446.1 12.0 201.5 302.6 252.0 71.5 1.7702
mmu-mir-15a-5p 619.3 469.9 544.6 105.7 226.7 301.7 264.2 53.1 2.0615
mmu-mir-181c-5p 108.9 112.6 110.7 2.6 80.7 300.8 190.7 155.7 0.5805
mmu-mir-802-5p 544.0 399.0 471.5 102.6 168.8 292.7 230.7 87.6 2.0435
mmu-mir-30a-3p 331.4 244.0 287.7 61.9 193.8 291.9 242.8 69.4 1.1847
mmu-mir-5115_-_8 218.5 1049.8 634.2 587.8 2060.1 280.7 1170.4 1258.2 0.5418
mmu-mir-142-5p 116.5 226.7 171.6 77.9 76.6 267.2 171.9 134.8 0.9980
mmu-mir-378-3p_+_1 274.5 262.6 268.5 8.4 170.2 260.4 215.3 63.8 1.2471
mmu-mir-328-3p 177.9 184.3 181.1 4.5 188.8 259.3 224.1 49.9 0.8082
mmu-mir-5115_-_5 123.1 419.3 271.2 209.4 302.8 252.7 277.7 35.4 0.9764
mmu-mir-152-3p 286.1 191.8 238.9 66.7 147.6 242.1 194.8 66.8 1.2262
mmu-mir-203-3p 415.6 303.2 359.4 79.5 185.5 232.8 209.1 33.5 1.7186
mmu-mir-139-5p 141.4 146.1 143.7 3.4 159.0 232.6 195.8 52.1 0.7342
mmu-mir-5115_-_7 118.8 387.6 253.2 190.0 707.4 225.4 466.4 340.8 0.5429
mmu-mir-451 497.8 1456.3 977.1 677.8 373.0 223.4 298.2 105.8 3.2769
mmu-mir-30a-3p_+_1 266.9 195.0 231.0 50.9 152.5 220.3 186.4 47.9 1.2393
mmu-mir-1839-5p 167.5 138.4 152.9 20.5 98.8 217.3 158.1 83.8 0.9676
mmu-mir-34a-5p 49.6 35.9 42.7 9.7 20.8 212.4 116.6 135.5 0.3666
mmu-mir-652-3p 65.9 96.6 81.3 21.7 95.6 206.1 150.9 78.1 0.5385
mmu-mir-676-3p 112.0 102.9 107.4 6.4 120.7 199.4 160.1 55.6 0.6711
mmu-mir-98-5p 248.0 170.3 209.2 54.9 105.1 198.3 151.7 66.0 1.3788
Page 32 of 55
For Peer Review Only
Diabetes
mmu-mir-214-3p 32.1 30.1 31.1 1.4 34.5 198.2 116.4 115.8 0.2672
mmu-mir-195-5p 73.9 56.9 65.4 12.0 44.5 194.4 119.4 106.0 0.5474
mmu-mir-425-5p 156.0 155.1 155.5 0.6 91.8 193.1 142.4 71.7 1.0922
mmu-mir-203-3p_+_1 374.7 235.2 305.0 98.6 141.1 190.1 165.6 34.6 1.8419
mmu-mir-340-5p 243.9 227.8 235.9 11.3 105.7 188.9 147.3 58.8 1.6011
mmu-mir-29a-3p_-_1 115.6 104.7 110.2 7.7 79.2 187.6 133.4 76.6 0.8258
mmu-mir-22-3p_+_1 278.3 225.0 251.6 37.7 133.0 184.1 158.6 36.2 1.5870
mmu-mir-214-3p_-_1 23.2 18.9 21.0 3.1 26.3 183.7 105.0 111.4 0.2001
mmu-mir-149-5p 26.5 25.2 25.8 0.9 19.0 182.8 100.9 115.8 0.2560
mmu-mir-15b-5p 74.2 103.5 88.9 20.7 67.3 178.3 122.8 78.5 0.7236
mmu-mir-5109_+_5 120.4 314.2 217.3 137.0 409.7 171.8 290.8 168.3 0.7472
mmu-mir-30c-2-3p 156.3 139.6 148.0 11.8 145.0 164.7 154.8 13.9 0.9555
mmu-mir-532-5p 92.0 100.2 96.1 5.8 60.9 163.7 112.3 72.7 0.8556
mmu-mir-497-5p 43.8 38.3 41.1 3.8 30.3 160.2 95.3 91.9 0.4309
mmu-mir-342-3p 74.8 65.4 70.1 6.6 35.4 159.4 97.4 87.7 0.7192
mmu-mir-181b-2-5p 66.0 57.8 61.9 5.8 59.3 159.0 109.2 70.5 0.5671
mmu-mir-145-5p 93.5 86.6 90.0 4.9 89.1 158.1 123.6 48.8 0.7282
mmu-mir-143-3p_-_1 94.8 63.8 79.3 21.9 45.5 152.8 99.2 75.8 0.7996
mmu-mir-181b-1-5p 62.6 54.2 58.4 5.9 55.9 151.1 103.5 67.3 0.5645
mmu-mir-146b-5p 52.2 34.1 43.2 12.9 21.2 150.3 85.8 91.3 0.5031
mmu-mir-30e-3p 229.4 150.0 189.7 56.1 109.9 148.4 129.1 27.3 1.4690
mmu-mir-148a-5p 123.9 155.5 139.7 22.3 90.2 147.7 119.0 40.6 1.1739
mmu-mir-92b-3p 24.2 18.0 21.1 4.4 24.2 146.2 85.2 86.3 0.2481
mmu-mir-199a-1-5p 29.7 32.6 31.1 2.0 25.2 143.2 84.2 83.4 0.3697
mmu-mir-199a-2-5p 29.7 32.6 31.1 2.0 25.2 143.2 84.2 83.4 0.3697
mmu-mir-122-3p 206.0 173.0 189.5 23.3 109.7 143.0 126.3 23.5 1.5003
mmu-mir-30a-5p_+_1 196.8 172.4 184.6 17.3 95.6 140.6 118.1 31.8 1.5632
mmu-mir-802-3p 140.5 112.3 126.4 19.9 64.7 138.2 101.4 51.9 1.2458
mmu-mir-361-5p 126.0 104.3 115.2 15.4 80.1 137.7 108.9 40.7 1.0577
mmu-mir-29c-3p 242.7 236.7 239.7 4.3 115.7 133.7 124.7 12.7 1.9220
mmu-mir-222-3p 79.9 86.9 83.4 4.9 68.3 131.7 100.0 44.9 0.8339
mmu-mir-92a-1-3p_+_1 74.1 76.4 75.3 1.6 74.3 128.3 101.3 38.2 0.7427
mmu-mir-574-3p 85.0 72.7 78.8 8.7 65.0 122.2 93.6 40.4 0.8423
mmu-mir-17-5p 78.6 63.1 70.9 11.0 43.0 119.1 81.0 53.8 0.8747
mmu-mir-5115_-_3 62.8 202.4 132.6 98.7 150.0 115.8 132.9 24.2 0.9979
mmu-mir-183-5p 44.6 51.7 48.1 5.0 66.7 112.9 89.8 32.6 0.5360
mmu-mir-671-3p 78.4 74.3 76.4 2.9 62.7 108.8 85.8 32.6 0.8903
mmu-mir-28-3p 93.6 80.3 86.9 9.5 67.6 107.4 87.5 28.1 0.9942
mmu-mir-10a-5p_-_1 93.8 69.9 81.8 16.8 43.1 105.2 74.1 44.0 1.1041
mmu-mir-5109_+_4 70.1 180.7 125.4 78.2 293.4 104.7 199.1 133.4 0.6301
mmu-mir-122-3p_+_1 184.5 168.2 176.3 11.5 93.9 103.2 98.6 6.6 1.7886
Page 33 of 55
For Peer Review Only
Diabetes
mmu-mir-423-3p_-_1 72.9 76.0 74.5 2.2 78.8 98.7 88.8 14.1 0.8389
mmu-mir-1839-5p_+_1 63.2 49.8 56.5 9.5 31.5 95.6 63.5 45.3 0.8892
mmu-mir-200a-3p 44.4 30.9 37.6 9.5 19.7 94.5 57.1 52.9 0.6592
mmu-mir-301a-3p 62.6 52.2 57.4 7.4 32.4 93.8 63.1 43.5 0.9093
mmu-mir-145-3p 62.3 53.9 58.1 5.9 33.9 92.3 63.1 41.3 0.9216
mmu-mir-326-3p 31.1 36.9 34.0 4.1 37.8 91.9 64.9 38.2 0.5237
mmu-mir-151-3p_-_1 39.4 43.4 41.4 2.8 50.3 91.2 70.7 29.0 0.5851
mmu-mir-322-5p 124.2 86.0 105.1 27.0 44.5 90.8 67.6 32.8 1.5540
mmu-mir-331-3p 40.6 46.7 43.7 4.3 54.9 88.9 71.9 24.0 0.6070
mmu-mir-1247-5p 149.0 93.5 121.3 39.3 174.7 86.1 130.4 62.7 0.9300
mmu-mir-20a-5p 57.6 58.2 57.9 0.4 29.5 85.7 57.6 39.7 1.0049
mmu-mir-132-3p 21.6 20.0 20.8 1.1 16.3 83.1 49.7 47.2 0.4186
mmu-mir-181a-2-3p_-_3 29.0 23.3 26.1 4.0 24.1 81.1 52.6 40.3 0.4970
mmu-mir-5109_+_3 58.1 143.6 100.9 60.5 219.8 80.8 150.3 98.3 0.6710
mmu-mir-5109_-_2 47.2 114.5 80.8 47.6 148.7 76.6 112.7 51.0 0.7175
mmu-mir-223-3p 37.6 36.5 37.1 0.7 17.7 75.9 46.8 41.2 0.7918
mmu-mir-5109_-_1 72.2 92.7 82.4 14.5 163.5 73.4 118.4 63.7 0.6960
mmu-mir-199a-2-3p_-_1 16.5 11.1 13.8 3.8 10.5 73.1 41.8 44.3 0.3301
mmu-mir-146a-5p_-_1 31.2 30.9 31.0 0.2 16.0 72.2 44.1 39.7 0.7026
mmu-mir-199a-1-3p_-_1 16.2 11.0 13.6 3.7 10.5 71.9 41.2 43.4 0.3299
mmu-mir-199b-3p_-_1 16.2 11.0 13.6 3.7 10.5 71.9 41.2 43.4 0.3299
mmu-mir-872-5p 65.9 48.5 57.2 12.3 31.0 70.1 50.6 27.6 1.1315
mmu-mir-1843-5p 93.6 95.0 94.3 1.0 53.6 68.3 61.0 10.4 1.5474
mmu-mir-181d-5p 21.2 21.4 21.3 0.1 18.5 66.4 42.4 33.9 0.5014
mmu-mir-455-3p 38.8 35.9 37.4 2.1 68.2 66.3 67.3 1.4 0.5559
mmu-mir-27b-3p_-_1 59.8 26.1 43.0 23.8 17.8 66.3 42.0 34.3 1.0224
mmu-mir-155-5p 7.4 5.5 6.5 1.4 5.3 65.6 35.5 42.6 0.1821
mmu-mir-322-3p 80.8 61.8 71.3 13.4 48.3 65.1 56.7 11.9 1.2572
mmu-mir-21-3p 19.6 24.8 22.2 3.7 13.3 64.5 38.9 36.2 0.5706
mmu-mir-421-3p 54.7 51.5 53.1 2.2 31.8 59.2 45.5 19.4 1.1670
mmu-mir-10b-5p 124.1 63.1 93.6 43.2 66.3 57.9 62.1 6.0 1.5073
mmu-mir-429-3p 30.6 14.0 22.3 11.7 12.3 57.4 34.8 31.9 0.6399
mmu-mir-221-5p 32.6 24.0 28.3 6.0 23.8 57.2 40.5 23.7 0.6987
mmu-mir-125b-2-3p 45.0 41.2 43.1 2.7 19.1 56.3 37.7 26.3 1.1438
mmu-mir-215-5p 2006.4 85.2 1045.8 1358.5 164.5 56.0 110.3 76.7 9.4852
mmu-mir-106b-5p 40.0 46.2 43.1 4.4 19.3 54.0 36.6 24.6 1.1777
mmu-mir-5105_+_7 61.7 71.1 66.4 6.6 60.3 52.3 56.3 5.6 1.1785
mmu-mir-122-5p_+_4 34.1 35.9 35.0 1.3 33.6 51.8 42.7 12.8 0.8195
mmu-mir-541-5p 11.3 8.8 10.1 1.8 6.1 50.6 28.4 31.5 0.3551
mmu-mir-24-2-5p 33.9 36.3 35.1 1.7 18.0 50.1 34.1 22.7 1.0307
mmu-let-7d-3p_+_1 35.4 35.1 35.3 0.3 36.2 49.9 43.0 9.7 0.8192
Page 34 of 55
For Peer Review Only
Diabetes
mmu-mir-5109_-_3 23.3 56.1 39.7 23.2 122.3 49.5 85.9 51.5 0.4625
mmu-mir-378-5p 41.9 43.6 42.8 1.2 38.2 49.3 43.8 7.8 0.9767
mmu-mir-22-5p 54.9 44.3 49.6 7.5 22.7 49.2 36.0 18.7 1.3790
mmu-mir-92a-1-5p 14.6 12.3 13.5 1.6 17.4 48.7 33.0 22.1 0.4077
mmu-mir-674-3p 37.0 33.8 35.4 2.2 25.3 48.4 36.8 16.3 0.9618
mmu-mir-30e-5p_+_1 71.4 67.8 69.6 2.5 36.3 46.4 41.4 7.1 1.6812
mmu-mir-199a-2-3p_+_1 15.3 11.1 13.2 3.0 8.0 46.0 27.0 26.9 0.4873
mmu-mir-874-3p 27.4 34.0 30.7 4.7 39.4 45.9 42.7 4.6 0.7193
mmu-mir-5109_+_7 20.2 38.6 29.4 13.0 122.5 45.6 84.1 54.4 0.3495
mmu-mir-126-3p_-_1 34.8 40.3 37.6 3.9 26.8 45.2 36.0 13.0 1.0436
mmu-mir-1249-3p 28.6 29.0 28.8 0.3 34.8 44.5 39.7 6.9 0.7253
mmu-mir-199a-1-3p_+_1 14.2 10.1 12.2 2.9 7.4 43.7 25.6 25.6 0.4765
mmu-mir-199b-3p_+_1 14.2 10.1 12.2 2.9 7.4 43.7 25.6 25.6 0.4765
mmu-mir-1948-3p 54.0 37.0 45.5 12.0 27.7 43.5 35.6 11.2 1.2770
mmu-mir-5109_+_8 19.6 47.3 33.5 19.5 84.2 42.5 63.3 29.4 0.5283
mmu-mir-1843b-5p_-_1 34.4 34.7 34.6 0.2 25.6 42.0 33.8 11.6 1.0226
mmu-mir-335-5p 40.7 36.3 38.5 3.1 16.8 41.5 29.2 17.5 1.3198
mmu-mir-151-5p_-_1 18.4 14.4 16.4 2.8 17.7 40.7 29.2 16.3 0.5620
mmu-mir-183-5p_+_1 12.1 11.7 11.9 0.3 16.3 38.0 27.1 15.4 0.4378
mmu-mir-144-3p 84.8 191.4 138.1 75.4 53.7 37.6 45.7 11.4 3.0244
mmu-mir-106b-3p 15.3 27.1 21.2 8.3 19.7 37.2 28.5 12.4 0.7454
mmu-mir-122-5p_+_3 28.6 26.0 27.3 1.8 28.4 36.5 32.5 5.7 0.8410
mmu-mir-339-3p 13.8 15.4 14.6 1.1 16.1 36.4 26.2 14.4 0.5570
mmu-mir-3096b-5p 4.8 4.7 4.7 0.0 8.5 36.0 22.2 19.5 0.2128
mmu-mir-194-2-3p 40.3 39.1 39.7 0.9 43.7 35.4 39.6 5.8 1.0038
mmu-mir-151-3p_-_2 18.0 18.5 18.3 0.3 14.1 35.3 24.7 15.0 0.7391
mmu-mir-1198-5p 27.2 28.6 27.9 0.9 26.5 34.5 30.5 5.6 0.9144
mmu-mir-141-3p 24.4 16.8 20.6 5.4 9.9 34.5 22.2 17.4 0.9276
mmu-mir-212-5p 4.3 6.5 5.4 1.5 6.5 34.2 20.3 19.6 0.2655
mmu-mir-151-3p_+_1 19.6 20.0 19.8 0.3 20.9 33.9 27.4 9.2 0.7239
mmu-mir-335-3p 23.0 20.8 21.9 1.5 12.6 33.3 22.9 14.7 0.9558
mmu-mir-1981-3p 35.3 23.8 29.5 8.1 17.3 33.3 25.3 11.3 1.1677
mmu-mir-5115_+_1 25.9 81.7 53.8 39.4 166.6 33.1 99.8 94.4 0.5390
mmu-mir-361-3p 20.1 20.1 20.1 0.0 16.0 32.1 24.1 11.4 0.8360
mmu-mir-10a-5p_+_2 30.7 23.3 27.0 5.2 14.1 32.1 23.1 12.7 1.1704
mmu-mir-128-1-3p 22.2 18.6 20.4 2.5 11.1 31.5 21.3 14.5 0.9566
mmu-mir-375-3p 107.4 45.1 76.2 44.0 88.7 31.3 60.0 40.5 1.2708
mmu-mir-23b-3p_+_1 37.0 26.9 32.0 7.1 23.8 31.0 27.4 5.1 1.1659
mmu-mir-21-5p_-_1 20.0 18.9 19.4 0.7 9.2 31.0 20.1 15.4 0.9674
mmu-mir-140-3p_+_2 21.9 23.3 22.6 1.0 14.4 30.8 22.6 11.6 1.0017
mmu-mir-144-5p 90.0 165.6 127.8 53.4 50.8 30.5 40.6 14.4 3.1455
Page 35 of 55
For Peer Review Only
Diabetes
mmu-mir-339-5p 8.2 12.8 10.5 3.3 13.2 29.8 21.5 11.8 0.4879
mmu-mir-3096-5p_+_1 4.0 3.1 3.6 0.6 6.8 29.6 18.2 16.1 0.1972
mmu-let-7b-3p 31.6 25.2 28.4 4.5 28.0 28.8 28.4 0.6 0.9982
mmu-mir-26a-1-5p_+_1 23.8 14.1 19.0 6.8 12.8 28.8 20.8 11.3 0.9127
mmu-mir-26a-2-5p_+_1 23.8 14.1 19.0 6.8 12.8 28.8 20.8 11.3 0.9127
mmu-mir-19b-2-3p 27.5 37.6 32.6 7.1 16.9 28.8 22.9 8.4 1.4248
mmu-mir-365-2-3p 42.4 39.7 41.0 1.9 23.1 28.1 25.6 3.5 1.6007
mmu-mir-365-1-3p 42.3 39.6 40.9 1.9 23.0 28.0 25.5 3.6 1.6065
mmu-mir-101b-3p_+_1 50.3 43.7 47.0 4.7 21.4 27.9 24.6 4.7 1.9059
mmu-mir-19b-1-3p 25.8 36.8 31.3 7.8 16.3 27.7 22.0 8.0 1.4258
mmu-mir-192-5p_-_1 85.2 71.1 78.2 9.9 34.0 27.5 30.7 4.6 2.5428
mmu-mir-224-5p 7.3 2.5 4.9 3.4 2.6 27.4 15.0 17.5 0.3250
mmu-mir-30c-1-3p 26.3 19.1 22.7 5.1 19.4 27.1 23.2 5.4 0.9759
mmu-mir-320-3p_+_1 14.6 13.7 14.1 0.7 17.9 26.9 22.4 6.3 0.6321
mmu-mir-185-5p 38.7 27.4 33.0 7.9 21.6 26.6 24.1 3.5 1.3715
mmu-mir-5105_+_6 15.8 60.2 38.0 31.4 67.3 26.0 46.6 29.2 0.8149
mmu-mir-411-5p 6.8 5.9 6.3 0.6 4.8 25.9 15.4 14.9 0.4129
mmu-mir-99b-5p_+_1 6.0 5.0 5.5 0.7 7.8 25.7 16.7 12.7 0.3284
mmu-mir-5115_-_4 8.9 40.6 24.7 22.4 29.0 25.4 27.2 2.5 0.9095
mmu-mir-145-3p_-_1 16.2 13.6 14.9 1.8 9.2 25.1 17.2 11.3 0.8691
mmu-mir-212-3p 2.8 3.8 3.3 0.7 3.3 24.8 14.0 15.2 0.2325
mmu-mir-122-5p_+_1 16.3 13.9 15.1 1.7 13.4 24.5 18.9 7.9 0.7986
mmu-mir-187-3p 17.3 18.8 18.0 1.1 11.6 24.5 18.1 9.1 0.9985
mmu-mir-532-3p 11.0 13.2 12.1 1.6 11.0 24.3 17.6 9.4 0.6844
mmu-mir-122-5p_+_6 17.4 17.0 17.2 0.3 17.5 24.1 20.8 4.7 0.8256
mmu-mir-22-3p_-_1 28.5 24.4 26.5 2.9 14.7 24.0 19.4 6.6 1.3657
mmu-mir-193b-3p 5.6 7.1 6.4 1.1 11.3 23.9 17.6 8.9 0.3629
mmu-mir-125b-1-3p 5.5 6.3 5.9 0.6 5.5 23.6 14.6 12.8 0.4048
mmu-mir-802-5p_+_1 33.8 30.7 32.2 2.1 14.6 23.3 18.9 6.1 1.7028
mmu-mir-214-5p 3.4 3.8 3.6 0.3 3.0 23.3 13.1 14.3 0.2768
mmu-mir-122-5p_+_2 16.8 12.3 14.5 3.2 10.9 22.1 16.5 7.9 0.8814
mmu-mir-338-3p 27.2 20.6 23.9 4.6 12.3 21.8 17.1 6.7 1.3999
mmu-let-7d-5p_-_1 16.5 15.2 15.8 0.9 9.9 21.7 15.8 8.4 1.0014
mmu-mir-582-3p_+_1 0.7 0.0 0.3 0.5 0.0 21.5 10.8 15.2 0.0306
mmu-mir-142-3p_+_3 10.1 17.4 13.8 5.2 8.5 21.5 15.0 9.2 0.9205
mmu-mir-130b-3p 11.0 13.1 12.0 1.5 6.4 21.2 13.8 10.5 0.8707
mmu-mir-1981-5p 17.0 15.2 16.1 1.3 15.0 20.8 17.9 4.1 0.8987
mmu-mir-5115_+_3 15.1 44.3 29.7 20.7 42.8 20.5 31.7 15.7 0.9387
mmu-mir-872-3p 17.6 17.1 17.4 0.3 9.0 20.5 14.7 8.2 1.1773
mmu-mir-192-3p 35.5 37.0 36.2 1.1 20.3 20.0 20.2 0.2 1.7968
mmu-mir-27b-5p 14.5 10.6 12.6 2.8 8.5 20.0 14.2 8.1 0.8815
Page 36 of 55
For Peer Review Only
Diabetes
mmu-mir-361-3p_+_1 13.3 12.6 13.0 0.5 11.7 19.5 15.6 5.5 0.8306
mmu-mir-322-3p_-_2 24.6 17.2 20.9 5.2 13.1 19.4 16.2 4.5 1.2863
mmu-mir-1843-5p_+_1 17.5 20.9 19.2 2.4 11.1 18.9 15.0 5.5 1.2791
mmu-mir-122-5p_+_5 11.6 10.1 10.8 1.1 11.4 18.9 15.1 5.3 0.7148
mmu-let-7g-5p_-_1 21.0 13.1 17.0 5.5 12.4 18.8 15.6 4.6 1.0926
mmu-mir-142-3p 10.3 16.0 13.1 4.0 5.3 18.8 12.1 9.5 1.0859
mmu-mir-26b-3p 14.6 12.0 13.3 1.9 10.1 18.7 14.4 6.1 0.9235
mmu-mir-200b-3p_+_1 5.2 4.2 4.7 0.7 3.8 18.7 11.3 10.5 0.4178
mmu-mir-1843b-5p 17.4 20.5 19.0 2.1 11.1 18.6 14.8 5.3 1.2775
mmu-mir-3096b-5p_-_1 4.1 3.9 4.0 0.2 7.3 18.5 12.9 7.9 0.3117
mmu-mir-350-5p 6.7 7.9 7.3 0.9 11.1 18.4 14.7 5.1 0.4939
mmu-mir-674-5p 10.9 10.3 10.6 0.4 11.6 18.4 15.0 4.8 0.7091
mmu-mir-345-5p_-_1 15.3 20.3 17.8 3.5 12.3 18.2 15.3 4.2 1.1702
mmu-mir-5109_-_4 8.9 22.9 15.9 9.9 49.7 18.0 33.9 22.4 0.4705
mmu-mir-125a-5p_+_1 4.9 3.1 4.0 1.3 5.8 17.9 11.8 8.6 0.3408
mmu-mir-17-3p 8.0 10.3 9.2 1.6 7.0 17.0 12.0 7.1 0.7642
mmu-mir-184-3p 6.1 6.9 6.5 0.6 9.2 16.6 12.9 5.3 0.5009
mmu-mir-10a-3p 16.7 11.1 13.9 4.0 7.2 16.6 11.9 6.7 1.1689
mmu-mir-411-5p_-_1 5.9 4.1 5.0 1.2 2.9 16.6 9.7 9.8 0.5129
mmu-mir-34c-5p 2.8 2.9 2.9 0.0 2.4 16.4 9.4 9.9 0.3043
mmu-mir-1843b-3p_-_1 11.5 15.1 13.3 2.6 10.1 16.4 13.2 4.5 1.0029
mmu-mir-142-5p_-_3 11.1 11.8 11.5 0.5 4.3 16.1 10.2 8.4 1.1204
mmu-mir-92a-1-3p_+_2 7.2 5.7 6.4 1.0 8.6 15.8 12.2 5.1 0.5282
mmu-mir-1964-3p 7.5 6.3 6.9 0.8 6.8 15.5 11.2 6.2 0.6193
mmu-mir-511-3p 16.6 11.9 14.2 3.3 10.5 15.4 13.0 3.5 1.0983
mmu-mir-324-5p 5.5 8.1 6.8 1.9 7.9 15.4 11.7 5.3 0.5815
mmu-mir-1843b-5p_-_2 16.7 14.5 15.6 1.6 11.5 15.3 13.4 2.7 1.1660
mmu-mir-148a-3p_+_1 18.9 14.8 16.8 2.9 9.3 15.3 12.3 4.2 1.3684
mmu-mir-99b-3p 3.6 5.0 4.3 1.0 4.9 15.3 10.1 7.3 0.4249
mmu-mir-664-3p 15.3 14.1 14.7 0.8 9.8 14.9 12.3 3.7 1.1895
mmu-mir-30d-3p 19.4 16.9 18.1 1.7 9.5 14.8 12.1 3.7 1.4934
mmu-mir-128-2-3p 10.7 9.9 10.3 0.5 6.4 14.7 10.6 5.9 0.9740
mmu-mir-5105_-_2 10.9 14.2 12.5 2.4 36.7 14.6 25.6 15.6 0.4891
mmu-mir-5105_-_8 12.0 16.9 14.5 3.5 38.8 14.2 26.5 17.5 0.5457
mmu-mir-374-5p 16.8 12.7 14.8 2.9 8.7 14.0 11.3 3.8 1.3048
mmu-mir-324-3p_+_2 7.9 9.1 8.5 0.8 9.8 13.9 11.9 2.9 0.7173
mmu-mir-434-3p 4.4 3.9 4.1 0.3 3.0 13.8 8.4 7.7 0.4938
mmu-mir-5115_+_4 8.8 28.4 18.6 13.8 33.4 13.6 23.5 14.0 0.7925
mmu-mir-195-3p 4.6 5.2 4.9 0.5 6.2 13.6 9.9 5.2 0.4938
mmu-mir-29b-2-3p 19.0 21.9 20.5 2.0 8.9 13.5 11.2 3.3 1.8240
mmu-mir-3096-5p 3.1 2.5 2.8 0.4 5.0 13.4 9.2 6.0 0.3076
Page 37 of 55
For Peer Review Only
Diabetes
mmu-mir-5109_-_5 7.3 19.8 13.6 8.8 31.4 13.2 22.3 12.9 0.6087
mmu-mir-223-5p 1.9 2.8 2.4 0.7 1.5 13.0 7.2 8.2 0.3244
mmu-mir-101c_-_1 13.0 21.7 17.4 6.2 9.8 13.0 11.4 2.2 1.5223
mmu-mir-29b-1-3p 18.2 21.5 19.9 2.3 8.9 12.9 10.9 2.9 1.8222
mmu-mir-100-5p_+_1 3.6 3.6 3.6 0.0 2.8 12.7 7.8 7.0 0.4662
mmu-mir-5109_+_2 8.4 20.0 14.2 8.2 32.8 12.6 22.7 14.3 0.6253
mmu-mir-140-5p 11.8 12.9 12.3 0.8 4.5 12.5 8.5 5.6 1.4504
mmu-mir-455-5p 16.9 14.3 15.6 1.8 12.6 12.2 12.4 0.3 1.2611
mmu-mir-342-5p 3.8 4.3 4.0 0.3 3.3 12.1 7.7 6.2 0.5212
mmu-mir-210-3p 11.9 12.9 12.4 0.7 7.5 12.0 9.8 3.2 1.2669
mmu-mir-342-3p_+_2 3.4 5.3 4.3 1.3 1.9 11.9 6.9 7.1 0.6260
mmu-mir-122-5p_-_1 12.4 9.8 11.1 1.9 10.4 11.8 11.1 1.0 1.0028
mmu-mir-106b-3p_-_2 3.9 7.5 5.7 2.5 5.2 11.7 8.4 4.6 0.6732
mmu-mir-5115_+_5 7.9 25.6 16.7 12.6 34.4 11.4 22.9 16.3 0.7298
mmu-mir-30a-5p_+_2 13.8 11.1 12.5 1.9 7.6 11.4 9.5 2.7 1.3077
mmu-mir-30b-3p 7.4 6.7 7.1 0.5 5.9 11.1 8.5 3.7 0.8330
mmu-mir-5109_+_1 5.4 13.1 9.3 5.4 35.6 11.0 23.3 17.4 0.3973
mmu-mir-1947-5p 9.5 9.5 9.5 0.0 4.9 11.0 7.9 4.3 1.1956
mmu-mir-5109_-_6 7.9 18.5 13.2 7.5 31.3 10.9 21.1 14.4 0.6256
mmu-mir-5105_+_1 7.3 17.7 12.5 7.4 29.2 10.9 20.0 12.9 0.6247
mmu-mir-340-3p 13.4 12.9 13.2 0.3 5.2 10.9 8.0 4.1 1.6431
mmu-mir-5105_+_5 7.7 19.3 13.5 8.2 17.4 10.8 14.1 4.7 0.9574
mmu-mir-142-3p_+_1 4.3 7.6 5.9 2.4 2.8 10.6 6.7 5.6 0.8837
mmu-mir-10b-5p_+_1 19.1 9.1 14.1 7.1 13.9 10.5 12.2 2.4 1.1570
mmu-mir-152-5p 8.7 13.0 10.9 3.1 6.4 10.5 8.4 2.9 1.2849
mmu-mir-582-3p 0.0 0.0 0.0 0.0 0.0 10.5 5.2 7.4 0.0000
mmu-mir-193-3p 17.7 20.1 18.9 1.7 12.6 10.4 11.5 1.6 1.6482
mmu-mir-1843-3p 8.5 9.1 8.8 0.4 9.2 10.4 9.8 0.9 0.9017
mmu-mir-1843-5p_-_1 13.7 15.1 14.4 1.0 9.9 10.3 10.1 0.3 1.4269
mmu-mir-5109_-_8 6.2 13.5 9.8 5.1 20.2 10.2 15.2 7.1 0.6492
mmu-mir-5105_-_3 7.7 7.3 7.5 0.2 25.4 10.1 17.8 10.8 0.4222
mmu-mir-143-5p 3.5 3.5 3.5 0.0 4.7 10.0 7.4 3.8 0.4734
mmu-mir-25-5p 3.3 4.1 3.7 0.5 4.5 10.0 7.2 3.8 0.5080
mmu-mir-125b-2-3p_-_2 6.7 8.0 7.3 0.9 4.4 10.0 7.2 3.9 1.0168
mmu-mir-24-1-3p_+_1 4.4 3.8 4.1 0.4 3.2 9.8 6.5 4.7 0.6297
mmu-mir-24-2-3p_+_1 4.4 3.8 4.1 0.4 3.2 9.8 6.5 4.7 0.6297
mmu-mir-27b-3p_+_1 6.1 4.1 5.1 1.4 2.1 9.8 5.9 5.5 0.8640
mmu-mir-148b-5p 9.7 10.2 9.9 0.4 6.4 9.7 8.0 2.4 1.2385
mmu-mir-32-5p 14.6 10.6 12.6 2.8 4.7 9.7 7.2 3.5 1.7497
mmu-mir-181c-3p 3.8 3.6 3.7 0.1 1.7 9.6 5.7 5.6 0.6601
mmu-mir-455-3p_+_1 16.4 12.1 14.3 3.1 24.8 9.5 17.2 10.8 0.8308
Page 38 of 55
For Peer Review Only
Diabetes
mmu-mir-345-3p 8.5 7.5 8.0 0.7 6.4 9.5 8.0 2.2 1.0018
mmu-mir-142-5p_+_1 3.4 8.3 5.9 3.5 2.2 9.5 5.8 5.1 1.0052
mmu-mir-5115_+_2 4.4 20.8 12.6 11.6 62.7 9.5 36.1 37.7 0.3484
mmu-mir-671-5p 6.7 6.4 6.5 0.2 4.3 9.3 6.8 3.5 0.9579
mmu-mir-486-3p 13.4 28.3 20.8 10.6 17.0 9.2 13.1 5.5 1.5915
mmu-mir-5105_+_3 9.4 13.7 11.5 3.0 23.0 9.0 16.0 9.9 0.7198
mmu-mir-200c-3p 8.5 4.4 6.5 2.9 5.2 9.0 7.1 2.7 0.9110
mmu-mir-125a-3p 3.0 2.3 2.6 0.5 4.7 8.9 6.8 3.0 0.3880
mmu-let-7c-2-3p 11.5 10.5 11.0 0.7 4.5 8.8 6.6 3.1 1.6477
mmu-let-7a-1-3p 11.5 10.4 10.9 0.8 4.5 8.8 6.6 3.1 1.6469
mmu-mir-194-2-5p_-_1 19.4 13.0 16.2 4.5 8.9 8.8 8.8 0.1 1.8378
mmu-mir-148a-5p_-_1 7.9 8.4 8.1 0.4 5.5 8.8 7.1 2.3 1.1385
mmu-mir-205-5p 2.6 1.8 2.2 0.6 2.1 8.8 5.4 4.7 0.4006
mmu-mir-5109_-_7 6.1 18.6 12.3 8.8 21.8 8.7 15.3 9.3 0.8072
mmu-mir-486-5p_+_2 13.3 34.2 23.8 14.8 20.0 8.7 14.4 8.0 1.6526
mmu-mir-378-3p_-_1 9.4 5.3 7.3 2.9 4.5 8.6 6.5 2.9 1.1245
mmu-mir-664-5p 6.3 7.0 6.6 0.5 5.2 8.5 6.8 2.4 0.9719
mmu-mir-425-3p_-_1 7.6 5.9 6.7 1.2 4.9 8.2 6.6 2.4 1.0234
mmu-let-7i-3p 2.0 3.5 2.8 1.0 4.5 8.2 6.3 2.6 0.4371
mmu-mir-3102-3p 0.9 0.9 0.9 0.0 1.5 8.1 4.8 4.6 0.1829
mmu-mir-874-5p 5.0 5.3 5.2 0.2 4.7 8.0 6.4 2.3 0.8160
mmu-mir-5105_+_2 6.8 14.3 10.5 5.3 24.4 7.9 16.2 11.7 0.6518
mmu-mir-423-3p_+_1 5.0 4.9 5.0 0.1 4.9 7.8 6.4 2.0 0.7817
mmu-mir-151-3p_+_2 4.9 3.8 4.3 0.8 4.0 7.8 5.9 2.7 0.7285
mmu-mir-5109_+_6 4.6 10.0 7.3 3.8 21.5 7.7 14.6 9.7 0.4999
mmu-mir-322-3p_-_1 10.3 6.2 8.3 2.9 4.7 7.7 6.2 2.1 1.3250
mmu-mir-186-5p_+_1 8.2 7.0 7.6 0.9 3.2 7.7 5.5 3.2 1.3884
mmu-mir-3096b-5p_+_1 1.0 1.5 1.3 0.4 2.9 7.5 5.2 3.3 0.2429
mmu-mir-181a-1-3p 7.6 7.5 7.5 0.1 3.5 7.4 5.5 2.8 1.3760
mmu-mir-676-5p 7.5 7.9 7.7 0.3 2.6 7.3 5.0 3.3 1.5543
mmu-mir-3057-5p 5.4 3.9 4.7 1.0 7.9 7.2 7.6 0.5 0.6143
mmu-mir-181a-1-5p_+_1 2.8 2.3 2.6 0.3 2.5 7.2 4.8 3.4 0.5345
mmu-mir-181a-2-5p_+_1 2.8 2.3 2.6 0.3 2.5 7.2 4.8 3.4 0.5345
mmu-mir-700-3p 2.5 2.6 2.6 0.1 2.9 7.1 5.0 3.0 0.5164
mmu-mir-30d-5p_+_1 5.8 3.1 4.4 1.9 3.7 7.0 5.4 2.4 0.8288
mmu-mir-99a-5p_-_1 4.3 4.3 4.3 0.1 3.2 7.0 5.1 2.7 0.8436
mmu-mir-130a-3p_+_1 4.0 6.0 5.0 1.5 3.3 7.0 5.1 2.6 0.9726
mmu-mir-330-3p_+_1 5.2 4.4 4.8 0.5 4.2 6.8 5.5 1.8 0.8702
mmu-mir-320-3p_+_2 3.7 2.6 3.2 0.8 4.2 6.8 5.5 1.9 0.5807
mmu-mir-96-5p 4.0 4.4 4.2 0.3 3.8 6.8 5.3 2.1 0.7894
mmu-mir-5117-3p_-_4 2.3 2.6 2.5 0.3 3.2 6.7 5.0 2.5 0.4956
Page 39 of 55
For Peer Review Only
Diabetes
mmu-mir-345-5p 4.5 4.8 4.7 0.2 3.2 6.7 4.9 2.5 0.9479
mmu-mir-500-3p 3.1 3.9 3.5 0.6 3.1 6.7 4.9 2.5 0.7184
mmu-mir-30e-3p_+_1 11.6 7.1 9.4 3.2 5.3 6.7 6.0 1.0 1.5687
mmu-mir-3105-3p 10.4 9.2 9.8 0.9 4.4 6.5 5.4 1.5 1.8009
mmu-mir-547-3p 3.2 2.3 2.8 0.6 2.4 6.5 4.5 2.9 0.6242
mmu-mir-1948-3p_+_1 6.8 3.4 5.1 2.4 4.0 6.4 5.2 1.7 0.9819
mmu-mir-5126_-_1 2.6 4.8 3.7 1.5 10.3 6.4 8.3 2.8 0.4414
mmu-mir-324-3p 1.6 2.9 2.2 1.0 3.7 6.4 5.0 1.9 0.4454
mmu-mir-877-5p 3.7 3.1 3.4 0.4 3.3 6.4 4.8 2.2 0.6978
mmu-mir-18a-5p 3.8 5.1 4.5 0.9 1.9 6.4 4.1 3.2 1.0886
mmu-mir-450a-1-5p 7.2 5.8 6.5 1.0 4.5 6.3 5.4 1.3 1.2063
mmu-mir-450a-2-5p 7.2 5.2 6.2 1.5 4.5 6.3 5.4 1.3 1.1470
mmu-mir-511-5p_-_1 3.9 3.3 3.6 0.4 3.0 6.3 4.6 2.3 0.7762
mmu-mir-3096-5p_+_2 0.6 1.1 0.9 0.3 2.0 6.2 4.1 2.9 0.2104
mmu-mir-1843b-3p_-_3 4.0 6.0 5.0 1.4 3.0 6.2 4.6 2.3 1.0999
mmu-let-7e-3p 1.9 2.1 2.0 0.2 2.7 6.2 4.4 2.5 0.4581
mmu-let-7f-1-3p 7.8 6.7 7.2 0.8 3.8 6.1 4.9 1.6 1.4652
mmu-mir-200b-5p 2.0 0.8 1.4 0.9 0.7 6.0 3.4 3.8 0.4209
mmu-mir-15b-3p 5.9 7.4 6.7 1.0 2.4 5.9 4.1 2.5 1.6092
mmu-mir-5122_-_1 3.9 3.0 3.4 0.6 4.6 5.8 5.2 0.9 0.6592
mmu-mir-22-3p_+_2 9.3 3.7 6.5 4.0 3.8 5.8 4.8 1.4 1.3455
mmu-mir-542-3p 6.7 6.3 6.5 0.3 2.9 5.8 4.4 2.1 1.4916
mmu-mir-330-5p 4.8 5.1 4.9 0.2 3.2 5.8 4.5 1.9 1.1025
mmu-let-7c-1-5p_-_1 3.0 3.6 3.3 0.4 4.0 5.8 4.9 1.2 0.6718
mmu-mir-129-1-5p 1.1 0.9 1.0 0.1 1.4 5.8 3.6 3.1 0.2788
mmu-mir-29a-3p_+_5 2.9 2.7 2.8 0.1 2.3 5.7 4.0 2.4 0.6930
mmu-mir-129-2-5p 1.1 0.9 1.0 0.1 1.4 5.7 3.6 3.0 0.2822
mmu-mir-145-3p_-_2 4.0 2.2 3.1 1.3 1.5 5.7 3.6 3.0 0.8740
mmu-let-7f-2-5p_-_1 5.5 3.9 4.7 1.1 2.1 5.6 3.8 2.5 1.2221
mmu-mir-21-3p_+_1 3.8 4.1 3.9 0.2 1.6 5.6 3.6 2.8 1.0855
mmu-mir-5105_-_7 4.3 5.4 4.9 0.8 11.2 5.5 8.4 4.0 0.5819
mmu-mir-192-5p_+_2 9.3 4.8 7.0 3.2 4.8 5.5 5.2 0.5 1.3661
mmu-mir-345-3p_-_1 4.4 4.8 4.6 0.3 3.8 5.5 4.7 1.2 0.9894
mmu-mir-210-5p 4.0 3.3 3.6 0.5 3.3 5.5 4.4 1.6 0.8315
mmu-mir-125b-2-3p_-_3 2.5 2.8 2.7 0.2 2.0 5.5 3.7 2.5 0.7158
mmu-mir-127-3p_-_1 0.8 0.0 0.4 0.6 0.9 5.5 3.2 3.2 0.1217
mmu-mir-5105_+_4 2.5 4.7 3.6 1.5 7.7 5.4 6.5 1.6 0.5566
mmu-mir-219-1-3p 4.1 3.9 4.0 0.2 2.6 5.4 4.0 2.0 1.0044
mmu-let-7c-1-5p_+_1 2.5 2.9 2.7 0.3 2.5 5.4 3.9 2.1 0.6863
mmu-mir-5099_-_1 2.2 2.1 2.1 0.1 4.0 5.3 4.7 0.9 0.4592
mmu-mir-486-5p_-_1 8.5 25.7 17.1 12.1 13.6 5.2 9.4 5.9 1.8236
Page 40 of 55
For Peer Review Only
Diabetes
mmu-mir-3068-3p 3.4 4.1 3.7 0.5 2.0 5.2 3.6 2.3 1.0244
mmu-mir-700-5p 2.0 3.2 2.6 0.9 1.5 5.2 3.4 2.6 0.7673
mmu-mir-132-5p_+_1 1.7 1.6 1.7 0.0 1.0 5.2 3.1 3.0 0.5342
mmu-let-7c-2-5p_+_1 2.7 3.1 2.9 0.3 2.5 5.2 3.9 1.9 0.7564
mmu-mir-298-5p 1.6 1.1 1.3 0.3 1.3 5.2 3.3 2.7 0.4024
mmu-mir-28-3p_+_1 2.0 2.6 2.3 0.4 1.8 5.1 3.5 2.4 0.6703
mmu-mir-93-3p 2.3 2.7 2.5 0.3 1.6 5.1 3.4 2.5 0.7429
mmu-mir-21-3p_+_2 1.7 2.1 1.9 0.2 1.3 5.1 3.2 2.7 0.5864
mmu-mir-5105_-_6 3.5 4.4 4.0 0.6 8.9 5.1 7.0 2.7 0.5711
mmu-mir-362-5p 1.8 1.6 1.7 0.1 1.6 5.1 3.4 2.4 0.5126
mmu-mir-346-5p 0.0 0.9 0.4 0.6 1.2 5.1 3.1 2.8 0.1374
mmu-mir-222-3p_-_1 3.0 2.6 2.8 0.3 2.3 4.9 3.6 1.8 0.7824
mmu-mir-673-5p 1.0 0.0 0.5 0.7 0.8 4.9 2.9 2.9 0.1671
mmu-mir-582-5p 0.0 0.0 0.0 0.0 0.0 4.9 2.4 3.5 0.0000
mmu-mir-143-3p_+_3 2.5 2.2 2.3 0.2 1.5 4.9 3.2 2.4 0.7430
mmu-mir-29a-3p_+_4 5.1 4.4 4.8 0.5 3.4 4.8 4.1 1.0 1.1634
mmu-mir-152-5p_+_1 3.6 5.5 4.5 1.3 3.4 4.7 4.1 0.9 1.1182
mmu-mir-99a-5p_+_4 5.8 3.1 4.4 1.9 2.1 4.7 3.4 1.8 1.2986
mmu-mir-18a-3p 2.2 3.6 2.9 0.9 1.1 4.7 2.9 2.6 0.9938
mmu-mir-191-3p 3.1 1.4 2.3 1.2 0.9 4.7 2.8 2.7 0.8065
mmu-mir-130b-5p 1.3 1.3 1.3 0.0 0.9 4.7 2.8 2.7 0.4511
mmu-mir-5105_-_4 3.7 4.3 4.0 0.5 5.9 4.6 5.3 0.9 0.7561
mmu-mir-3068-3p_+_1 4.9 4.1 4.5 0.5 1.4 4.6 3.0 2.3 1.4899
mmu-mir-223-3p_+_1 1.7 2.0 1.8 0.2 1.3 4.6 2.9 2.3 0.6301
mmu-mir-1968-5p 4.8 5.2 5.0 0.3 4.2 4.5 4.4 0.3 1.1439
mmu-mir-1843b-3p_-_2 4.1 3.3 3.7 0.6 2.2 4.5 3.4 1.6 1.0820
mmu-mir-7a-1-5p 10.5 6.8 8.6 2.6 2.1 4.5 3.3 1.7 2.5913
mmu-mir-3107-5p_-_1 7.2 22.9 15.1 11.1 11.9 4.5 8.2 5.2 1.8488
mmu-mir-30e-5p_+_2 6.5 6.0 6.3 0.4 2.8 4.5 3.6 1.2 1.7251
mmu-mir-19a-3p 6.0 7.2 6.6 0.9 2.3 4.4 3.4 1.5 1.9733
mmu-mir-144-3p_-_1 9.0 23.3 16.1 10.2 6.5 4.4 5.5 1.5 2.9561
mmu-mir-23a-3p_-_1 2.3 1.8 2.1 0.4 1.5 4.4 2.9 2.0 0.6986
mmu-mir-181a-2-3p_-_4 0.0 0.0 0.0 0.0 0.0 4.4 2.2 3.1 0.0000
mmu-mir-409-5p 0.0 0.0 0.0 0.0 0.0 4.4 2.2 3.1 0.0000
mmu-mir-5105_-_1 3.3 7.3 5.3 2.8 14.7 4.3 9.5 7.3 0.5565
mmu-mir-338-5p 2.9 1.9 2.4 0.7 2.7 4.3 3.5 1.1 0.6836
mmu-mir-5099_+_3 2.4 1.8 2.1 0.4 2.0 4.3 3.1 1.6 0.6590
mmu-mir-148a-3p_+_2 8.0 5.3 6.7 1.9 3.1 4.2 3.7 0.8 1.8184
mmu-mir-1839-3p 5.5 5.5 5.5 0.0 2.2 4.2 3.2 1.4 1.7209
mmu-mir-425-3p 3.2 2.1 2.7 0.8 2.2 4.2 3.2 1.4 0.8297
mmu-mir-7a-2-5p 9.8 6.5 8.2 2.3 1.9 4.2 3.1 1.6 2.6591
Page 41 of 55
For Peer Review Only
Diabetes
mmu-mir-99b-5p_-_1 0.0 0.8 0.4 0.6 1.7 4.2 3.0 1.8 0.1326
mmu-mir-434-5p 0.7 0.9 0.8 0.2 0.7 4.2 2.5 2.5 0.3212
mmu-mir-339-3p_+_2 1.4 1.6 1.5 0.1 1.3 4.1 2.7 2.0 0.5639
mmu-mir-1964-3p_-_1 1.9 1.8 1.9 0.0 2.9 4.0 3.5 0.8 0.5340
mmu-mir-501-3p_+_1 1.8 0.0 0.9 1.3 1.9 4.0 3.0 1.5 0.3011
mmu-mir-574-5p 2.8 1.8 2.3 0.7 0.0 4.0 2.0 2.8 1.1501
mmu-mir-5099_+_1 2.2 1.8 2.0 0.2 2.1 4.0 3.1 1.3 0.6584
mmu-mir-1306-5p_+_2 1.4 2.6 2.0 0.9 2.8 3.9 3.4 0.8 0.5936
mmu-mir-126-5p_+_1 8.5 5.1 6.8 2.4 2.8 3.9 3.4 0.8 2.0150
mmu-mir-30c-2-3p_+_1 3.4 3.1 3.2 0.2 2.8 3.9 3.4 0.8 0.9630
mmu-mir-199b-5p 0.0 0.0 0.0 0.0 0.6 3.9 2.3 2.3 0.0000
mmu-mir-582-5p_+_1 0.0 0.0 0.0 0.0 0.0 3.9 1.9 2.7 0.0000
mmu-mir-92a-2-3p_+_1 2.7 2.3 2.5 0.3 2.7 3.7 3.2 0.7 0.7734
mmu-mir-22-3p_+_4 5.0 3.2 4.1 1.3 2.6 3.7 3.2 0.8 1.2997
mmu-mir-99a-3p 3.5 4.8 4.2 0.9 4.3 3.7 4.0 0.4 1.0474
mmu-mir-187-5p 2.2 2.1 2.1 0.1 2.9 3.7 3.3 0.6 0.6546
mmu-mir-450b-5p 6.0 3.8 4.9 1.6 1.4 3.7 2.5 1.6 1.9205
mmu-mir-702 2.5 0.8 1.6 1.2 1.3 3.7 2.5 1.7 0.6529
mmu-mir-5102_-_3 3.5 2.8 3.2 0.5 15.3 3.7 9.5 8.2 0.3350
mmu-mir-5099 1.2 2.0 1.6 0.6 2.8 3.6 3.2 0.6 0.5118
mmu-mir-31-3p 1.6 2.3 1.9 0.5 0.7 3.6 2.2 2.0 0.8854
mmu-mir-379-5p 0.0 0.0 0.0 0.0 0.0 3.6 1.8 2.5 0.0000
mmu-mir-877-3p 2.6 3.3 3.0 0.5 2.0 3.6 2.8 1.1 1.0603
mmu-mir-3107-5p_+_2 5.8 14.6 10.2 6.2 8.2 3.6 5.9 3.3 1.7257
mmu-mir-148a-3p_-_1 4.4 2.9 3.7 1.1 2.0 3.5 2.8 1.1 1.3322
mmu-mir-21-5p_+_1 2.7 2.6 2.6 0.1 1.0 3.5 2.3 1.8 1.1560
mmu-mir-136-3p_-_1 1.7 1.4 1.5 0.3 0.0 3.5 1.8 2.5 0.8783
mmu-mir-5105_-_5 1.1 3.9 2.5 2.0 3.8 3.4 3.6 0.3 0.6883
mmu-mir-5117-5p 0.8 0.0 0.4 0.6 1.3 3.4 2.4 1.5 0.1783
mmu-mir-362-3p 1.6 2.3 1.9 0.5 1.0 3.4 2.2 1.7 0.8593
mmu-mir-378b_-_1 3.4 3.9 3.7 0.3 1.9 3.4 2.6 1.0 1.3947
mmu-mir-193-5p 4.3 4.6 4.5 0.2 4.0 3.3 3.7 0.5 1.2166
mmu-mir-30d-3p_+_1 6.7 4.8 5.8 1.4 2.4 3.3 2.9 0.7 1.9941
mmu-mir-190-5p 6.4 3.7 5.0 1.9 1.5 3.3 2.4 1.3 2.0702
mmu-mir-211-5p 0.9 0.0 0.4 0.6 0.7 3.3 2.0 1.9 0.2240
mmu-mir-181b-2-5p_+_1 0.7 1.2 1.0 0.3 1.2 3.3 2.3 1.5 0.4258
mmu-let-7f-1-5p_-_1 3.1 2.2 2.7 0.6 1.3 3.3 2.3 1.4 1.1469
mmu-mir-652-3p_+_1 0.0 0.0 0.0 0.0 1.2 3.3 2.2 1.4 0.0000
mmu-mir-99b-5p_+_4 1.4 1.2 1.3 0.1 1.1 3.3 2.2 1.5 0.5947
mmu-mir-470-5p 1.0 0.0 0.5 0.7 0.8 3.3 2.0 1.7 0.2369
mmu-mir-143-3p_+_1 2.9 1.1 2.0 1.3 0.0 3.3 1.6 2.3 1.2281
Page 42 of 55
For Peer Review Only
Diabetes
mmu-mir-194-2-3p_+_1 4.4 2.6 3.5 1.3 3.8 3.2 3.5 0.5 0.9917
mmu-mir-1943-5p_+_1 1.7 1.8 1.8 0.1 2.5 3.2 2.8 0.5 0.6232
mmu-mir-3073b-3p 1.4 1.7 1.6 0.2 2.1 3.2 2.6 0.8 0.6008
mmu-mir-29a-3p_+_6 2.3 1.8 2.1 0.4 1.9 3.2 2.5 0.9 0.8144
mmu-mir-871-3p 0.8 1.6 1.2 0.5 1.7 3.2 2.4 1.0 0.5007
mmu-mir-350-3p 2.3 2.6 2.5 0.2 1.1 3.2 2.1 1.5 1.1649
mmu-mir-212-5p_+_1 0.0 0.0 0.0 0.0 1.1 3.2 2.1 1.5 0.0000
mmu-mir-191-3p_+_1 2.9 1.8 2.4 0.7 1.6 3.1 2.3 1.1 1.0131
mmu-mir-5115_+_6 2.2 7.0 4.6 3.3 7.0 3.0 5.0 2.8 0.9247
mmu-mir-744-3p 4.6 3.9 4.3 0.5 2.4 3.0 2.7 0.4 1.5710
mmu-mir-222-5p 2.0 2.0 2.0 0.0 1.2 3.0 2.1 1.3 0.9698
mmu-mir-134-5p 0.0 0.0 0.0 0.0 0.0 3.0 1.5 2.1 0.0000
mmu-mir-30a-5p_+_8 3.2 3.9 3.5 0.5 1.3 3.0 2.1 1.2 1.6433
mmu-mir-181b-1-5p_+_1 0.7 1.0 0.8 0.2 1.0 3.0 2.0 1.4 0.4133
mmu-mir-7a-1-3p 5.0 3.3 4.2 1.2 1.5 2.9 2.2 1.0 1.9161
mmu-mir-29a-5p 2.8 3.0 2.9 0.2 1.3 2.9 2.1 1.2 1.3709
mmu-mir-342-5p_+_1 1.1 1.6 1.4 0.4 1.2 2.9 2.1 1.2 0.6574
mmu-let-7f-2-5p_+_5 1.7 1.3 1.5 0.3 1.1 2.9 2.0 1.3 0.7598
mmu-mir-139-3p 1.3 1.6 1.5 0.2 1.8 2.8 2.3 0.7 0.6354
mmu-mir-5117-3p_-_6 0.0 1.0 0.5 0.7 1.2 2.8 2.0 1.2 0.2500
mmu-mir-511-3p_+_1 1.4 1.6 1.5 0.1 1.0 2.8 1.9 1.3 0.7743
mmu-mir-337-5p_+_3 0.0 0.0 0.0 0.0 0.0 2.8 1.4 2.0 0.0000
mmu-mir-300-3p 0.0 0.0 0.0 0.0 0.0 2.8 1.4 2.0 0.0000
mmu-mir-3073b-5p 3.2 2.2 2.7 0.7 1.3 2.8 2.1 1.0 1.3055
mmu-mir-467d-5p 1.3 0.0 0.6 0.9 0.7 2.8 1.7 1.5 0.3643
mmu-mir-503-3p_-_1 2.2 1.4 1.8 0.5 2.3 2.7 2.5 0.3 0.7091
mmu-mir-335-3p_-_1 3.7 2.6 3.1 0.7 1.6 2.7 2.2 0.8 1.4348
mmu-mir-1839-5p_-_1 2.0 2.1 2.1 0.0 1.6 2.7 2.2 0.8 0.9488
mmu-mir-331-3p_+_1 1.3 2.2 1.7 0.7 1.5 2.7 2.1 0.9 0.8246
mmu-mir-29b-1-5p 1.3 1.5 1.4 0.1 1.2 2.7 1.9 1.1 0.7293
mmu-mir-25-3p_+_1 1.2 1.1 1.2 0.0 0.0 2.7 1.4 1.9 0.8511
mmu-mir-125b-1-5p_+_4 1.2 1.4 1.3 0.1 0.9 2.7 1.8 1.2 0.7084
mmu-mir-33-5p 4.7 4.3 4.5 0.2 3.0 2.7 2.8 0.3 1.5839
mmu-mir-99b-5p_+_3 1.5 0.0 0.7 1.1 0.8 2.7 1.8 1.3 0.4271
mmu-mir-125b-2-5p_+_4 1.2 1.1 1.2 0.0 0.9 2.6 1.7 1.2 0.6599
mmu-mir-203-5p 3.7 2.5 3.1 0.8 1.8 2.6 2.2 0.5 1.3990
mmu-mir-320-3p_-_1 1.2 1.0 1.1 0.1 1.6 2.6 2.1 0.7 0.5288
mmu-mir-5121_+_1 2.2 1.1 1.7 0.7 1.2 2.6 1.9 1.0 0.8783
mmu-mir-409-3p_-_1 0.0 0.0 0.0 0.0 0.0 2.6 1.3 1.8 0.0000
mmu-mir-5105 3.3 3.1 3.2 0.1 13.8 2.5 8.2 8.0 0.3940
mmu-mir-185-3p 1.7 1.4 1.5 0.3 1.5 2.5 2.0 0.7 0.7717
Page 43 of 55
For Peer Review Only
Diabetes
mmu-mir-664-5p_-_1 2.2 2.6 2.4 0.3 1.1 2.5 1.8 1.0 1.3182
mmu-mir-214-3p_-_2 0.0 0.0 0.0 0.0 0.0 2.4 1.2 1.7 0.0000
mmu-mir-29c-5p_+_2 2.4 3.6 3.0 0.9 1.8 2.4 2.1 0.4 1.4273
mmu-mir-598-3p 1.6 1.8 1.7 0.2 1.7 2.4 2.1 0.5 0.8138
mmu-mir-351-3p_+_1 1.0 0.9 0.9 0.0 1.7 2.4 2.1 0.5 0.4594
mmu-mir-10a-5p_+_3 2.1 1.1 1.6 0.7 1.1 2.4 1.7 0.9 0.9059
mmu-mir-677-5p_-_1 1.1 0.9 1.0 0.1 1.1 2.4 1.7 0.9 0.5735
mmu-mir-497-5p_+_1 0.8 0.0 0.4 0.6 0.0 2.4 1.2 1.7 0.3243
mmu-mir-363-3p 0.0 0.0 0.0 0.0 0.0 2.4 1.2 1.7 0.0000
mmu-mir-409-3p 0.0 0.0 0.0 0.0 0.0 2.4 1.2 1.7 0.0000
mmu-let-7f-1-5p_+_5 1.5 0.9 1.2 0.4 0.9 2.4 1.6 1.1 0.7397
mmu-let-7c-2-5p_+_5 1.0 1.2 1.1 0.1 0.9 2.4 1.7 1.0 0.6879
mmu-mir-5102_-_6 2.3 2.5 2.4 0.1 28.6 2.4 15.5 18.5 0.1551
mmu-let-7a-1-5p_+_5 1.5 1.7 1.6 0.1 1.1 2.4 1.7 0.9 0.9171
mmu-mir-5109 1.2 2.8 2.0 1.1 5.7 2.3 4.0 2.4 0.5013
mmu-mir-378-3p_+_2 2.8 1.4 2.1 1.0 1.9 2.3 2.1 0.3 0.9776
mmu-mir-503-3p 2.5 2.6 2.5 0.1 1.9 2.3 2.1 0.3 1.1956
mmu-mir-99b-5p_+_2 0.0 0.0 0.0 0.0 1.0 2.3 1.6 1.0 0.0000
mmu-mir-421-3p_+_1 1.7 1.8 1.8 0.0 0.0 2.3 1.2 1.6 1.5180
mmu-mir-501-3p_+_2 0.0 0.0 0.0 0.0 0.0 2.3 1.2 1.6 0.0000
mmu-mir-322-5p_-_1 1.7 1.0 1.4 0.5 1.2 2.2 1.7 0.8 0.8082
mmu-mir-188-5p 0.9 0.9 0.9 0.0 1.0 2.2 1.6 0.9 0.5698
mmu-mir-542-5p 1.3 1.6 1.4 0.2 0.8 2.2 1.5 1.0 0.9353
mmu-mir-3082-3p_+_1 1.2 1.6 1.4 0.3 0.7 2.2 1.5 1.1 0.9342
mmu-mir-5114 0.0 0.0 0.0 0.0 0.0 2.2 1.1 1.6 0.0000
mmu-let-7c-1-5p_+_5 1.0 1.2 1.1 0.1 1.0 2.2 1.6 0.9 0.7006
mmu-let-7a-2-5p_+_5 1.4 1.7 1.6 0.2 1.1 2.2 1.6 0.8 0.9554
mmu-mir-103-2-3p_+_2 1.2 1.4 1.3 0.1 0.9 2.2 1.5 0.9 0.8400
mmu-mir-103-1-3p_+_2 1.2 1.2 1.2 0.0 0.8 2.2 1.5 1.0 0.8017
mmu-mir-122-3p_-_2 3.4 2.6 3.0 0.6 1.7 2.1 1.9 0.3 1.5399
mmu-mir-3082-3p 1.4 1.4 1.4 0.0 1.6 2.1 1.9 0.4 0.7565
mmu-mir-423-5p_+_2 1.6 1.8 1.7 0.2 0.9 2.1 1.5 0.9 1.0924
mmu-mir-5102_-_5 2.0 3.1 2.5 0.8 15.3 2.1 8.7 9.3 0.2903
mmu-mir-92a-1-3p_-_1 1.0 0.8 0.9 0.1 0.8 2.1 1.5 0.9 0.6003
mmu-let-7c-1-5p_+_3 0.8 1.3 1.1 0.4 1.6 2.1 1.9 0.3 0.5705
mmu-mir-26b-5p_+_1 2.5 0.8 1.6 1.2 0.9 2.1 1.5 0.8 1.0955
mmu-mir-215-5p_+_1 11.8 5.9 8.9 4.2 2.9 2.1 2.5 0.6 3.5993
mmu-mir-671-3p_-_1 0.0 0.0 0.0 0.0 1.1 2.1 1.6 0.7 0.0000
mmu-mir-1955-5p 0.7 1.0 0.8 0.2 0.7 2.1 1.4 0.9 0.6011
mmu-mir-5107_-_1 0.0 0.0 0.0 0.0 0.0 2.1 1.0 1.5 0.0000
mmu-mir-540-3p 0.0 0.0 0.0 0.0 0.0 2.1 1.0 1.5 0.0000
Page 44 of 55
For Peer Review Only
Diabetes
mmu-let-7c-2-5p_+_3 0.8 1.5 1.1 0.4 1.6 2.0 1.8 0.3 0.6313
mmu-mir-3473d_+_1 2.0 2.3 2.1 0.2 1.6 2.0 1.8 0.3 1.1783
mmu-mir-150-3p 0.0 0.0 0.0 0.0 0.8 2.0 1.4 0.8 0.0000
mmu-mir-23a-3p_+_1 1.3 1.1 1.2 0.2 0.0 1.9 1.0 1.4 1.2542
mmu-mir-345-5p_+_2 1.4 2.1 1.8 0.5 1.5 1.9 1.7 0.3 1.0497
mmu-mir-183-3p_+_1 1.0 0.9 0.9 0.1 1.3 1.9 1.6 0.4 0.5735
mmu-mir-142-3p_+_2 0.7 1.4 1.0 0.5 0.0 1.9 0.9 1.3 1.0841
mmu-mir-142-5p_-_1 0.0 1.3 0.6 0.9 0.0 1.9 0.9 1.3 0.6783
mmu-mir-24-2-3p_-_1 0.9 0.0 0.4 0.6 0.0 1.8 0.9 1.3 0.4711
mmu-mir-24-1-3p_-_1 0.9 0.0 0.4 0.6 0.0 1.8 0.9 1.3 0.4711
mmu-mir-5102_-_1 2.7 2.3 2.5 0.3 4.5 1.8 3.1 1.9 0.8071
mmu-mir-677-5p 1.3 1.2 1.2 0.0 1.3 1.8 1.5 0.4 0.8026
mmu-mir-136-5p 0.7 0.0 0.4 0.5 0.0 1.8 0.9 1.3 0.3992
mmu-mir-423-3p_-_2 0.0 0.0 0.0 0.0 0.0 1.8 0.9 1.3 0.0000
mmu-mir-5114_-_1 0.0 0.0 0.0 0.0 0.0 1.8 0.9 1.3 0.0000
mmu-mir-125b-1-3p_-_1 0.0 0.0 0.0 0.0 0.0 1.8 0.9 1.3 0.0000
mmu-let-7a-2-5p_-_1 1.2 1.4 1.3 0.2 1.3 1.8 1.5 0.3 0.8393
mmu-mir-101b-3p_+_2 3.9 2.9 3.4 0.6 2.1 1.7 1.9 0.2 1.7983
mmu-mir-674-5p_+_1 0.0 0.9 0.5 0.7 1.7 1.7 1.7 0.0 0.2709
mmu-mir-99a-5p_+_3 2.2 0.9 1.5 0.9 1.2 1.7 1.4 0.4 1.0500
mmu-mir-101a-5p_+_1 1.9 2.8 2.4 0.7 1.0 1.7 1.4 0.5 1.7124
mmu-mir-1948-5p_+_1 4.9 2.8 3.9 1.5 0.9 1.7 1.3 0.5 2.9065
mmu-mir-143-3p_-_2 0.9 0.0 0.4 0.6 0.9 1.7 1.3 0.6 0.3424
mmu-mir-125a-5p_+_2 0.0 0.0 0.0 0.0 0.9 1.7 1.3 0.6 0.0000
mmu-mir-28-5p_-_1 1.0 0.9 1.0 0.1 0.8 1.7 1.3 0.7 0.7762
mmu-let-7a-2-5p_+_6 1.0 0.0 0.5 0.7 0.7 1.7 1.2 0.7 0.3999
mmu-let-7a-1-5p_+_6 0.8 0.0 0.4 0.6 0.7 1.7 1.2 0.7 0.3504
mmu-mir-100-5p_+_3 1.1 0.0 0.6 0.8 0.0 1.7 0.9 1.2 0.6636
mmu-mir-140-3p_+_4 1.1 0.0 0.5 0.8 0.0 1.7 0.9 1.2 0.6287
mmu-mir-378-5p_+_1 1.5 1.4 1.4 0.1 1.2 1.7 1.4 0.3 1.0106
mmu-mir-3068-3p_+_2 3.9 2.8 3.4 0.7 3.2 1.6 2.4 1.1 1.4094
mmu-mir-351-3p 0.9 1.3 1.1 0.3 1.8 1.6 1.7 0.1 0.6319
mmu-mir-137-3p 2.9 2.1 2.5 0.5 1.6 1.6 1.6 0.0 1.5337
mmu-mir-101b-5p_+_1 0.8 1.6 1.2 0.6 1.6 1.6 1.6 0.0 0.7719
mmu-mir-3073b-3p_-_1 0.9 1.0 0.9 0.1 1.1 1.6 1.4 0.4 0.6963
mmu-mir-802-3p_+_1 2.2 2.8 2.5 0.4 0.7 1.6 1.2 0.6 2.0918
mmu-mir-210-3p_-_1 1.4 1.4 1.4 0.0 0.7 1.6 1.2 0.6 1.1881
mmu-mir-467d-5p_-_1 0.6 0.0 0.3 0.4 0.7 1.6 1.2 0.6 0.2669
mmu-mir-3068-5p 0.0 1.1 0.5 0.8 0.7 1.6 1.1 0.7 0.4645
mmu-mir-10a-3p_+_1 1.0 0.8 0.9 0.1 0.0 1.6 0.8 1.2 1.0683
mmu-let-7c-2-5p_+_4 0.7 0.8 0.8 0.0 0.7 1.6 1.2 0.6 0.6464
Page 45 of 55
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Diabetes
mmu-let-7a-1-5p_-_1 1.4 1.3 1.3 0.1 1.3 1.6 1.4 0.2 0.9211
mmu-mir-133a-2-3p 0.9 0.0 0.5 0.7 1.1 1.6 1.3 0.4 0.3560
mmu-mir-133a-1-3p 0.9 0.0 0.5 0.7 1.1 1.6 1.3 0.4 0.3560
mmu-mir-5099_+_4 0.0 0.0 0.0 0.0 0.9 1.6 1.2 0.5 0.0000
mmu-mir-455-3p_-_2 1.1 2.6 1.8 1.0 2.2 1.5 1.9 0.5 0.9765
mmu-mir-26a-2-3p 2.9 1.3 2.1 1.2 1.3 1.5 1.4 0.2 1.4968
mmu-mir-101a-5p 1.8 1.9 1.9 0.1 1.2 1.5 1.3 0.3 1.3866
mmu-mir-674-5p_-_1 1.0 0.8 0.9 0.2 1.0 1.5 1.3 0.4 0.6995
mmu-mir-21-5p_+_4 0.0 0.9 0.5 0.7 0.9 1.5 1.2 0.5 0.3816
mmu-mir-23b-3p_-_1 1.2 1.0 1.1 0.1 0.7 1.5 1.1 0.6 0.9924
mmu-mir-200a-5p 0.0 0.0 0.0 0.0 0.7 1.5 1.1 0.6 0.0000
mmu-mir-148a-3p_+_4 2.2 1.3 1.7 0.7 0.0 1.5 0.8 1.1 2.2650
mmu-mir-23b-3p_+_3 1.0 1.1 1.1 0.0 0.0 1.5 0.8 1.1 1.3700
mmu-mir-93-5p_+_1 1.1 0.9 1.0 0.2 0.0 1.5 0.8 1.1 1.2901
mmu-mir-5117-3p_+_1 0.0 0.0 0.0 0.0 0.0 1.5 0.8 1.1 0.0000
mmu-mir-181d-3p_+_1 0.0 0.0 0.0 0.0 0.0 1.5 0.8 1.1 0.0000
mmu-mir-431-5p 0.0 0.0 0.0 0.0 0.0 1.5 0.8 1.1 0.0000
mmu-let-7c-1-5p_+_4 0.7 0.0 0.3 0.5 0.6 1.5 1.1 0.6 0.3029
mmu-let-7f-2-5p_+_1 1.8 0.9 1.4 0.6 0.8 1.5 1.1 0.5 1.1826
mmu-let-7f-2-5p_+_6 1.5 0.8 1.2 0.5 0.0 1.5 0.7 1.1 1.5464
mmu-mir-27b-3p_+_4 2.0 0.0 1.0 1.4 0.0 1.5 0.7 1.0 1.3506
mmu-mir-29c-5p 1.8 1.3 1.5 0.4 1.0 1.5 1.2 0.3 1.2367
mmu-mir-3076-3p 1.0 0.9 1.0 0.1 0.9 1.5 1.2 0.4 0.8208
mmu-mir-133a-2-3p_+_1 0.8 0.0 0.4 0.6 0.8 1.5 1.1 0.5 0.3569
mmu-mir-133a-1-3p_+_1 0.8 0.0 0.4 0.6 0.8 1.5 1.1 0.5 0.3569
mmu-mir-122-3p_-_1 1.5 1.3 1.4 0.2 0.8 1.5 1.1 0.5 1.2368
mmu-mir-106b-3p_-_1 0.0 1.0 0.5 0.7 0.8 1.5 1.1 0.5 0.4432
mmu-mir-140-3p_+_3 1.6 1.4 1.5 0.1 0.0 1.5 0.7 1.0 2.0438
mmu-mir-187-3p_-_1 0.9 1.1 1.0 0.2 0.0 1.5 0.7 1.0 1.3967
mmu-mir-143-3p_+_2 0.8 0.0 0.4 0.6 0.0 1.5 0.7 1.0 0.5548
mmu-mir-3061-3p 0.7 0.0 0.3 0.5 0.0 1.5 0.7 1.0 0.4520
mmu-mir-125b-2-5p_+_2 0.7 0.0 0.3 0.5 0.0 1.5 0.7 1.0 0.4520
mmu-mir-125b-1-5p_+_2 0.7 0.0 0.3 0.5 0.0 1.5 0.7 1.0 0.4520
mmu-mir-381-3p 0.0 0.0 0.0 0.0 0.0 1.5 0.7 1.0 0.0000
mmu-mir-410-3p 0.0 0.0 0.0 0.0 0.0 1.5 0.7 1.0 0.0000
mmu-let-7a-2-5p_+_3 1.1 0.9 1.0 0.2 1.0 1.4 1.2 0.3 0.8409
mmu-let-7f-1-5p_+_1 1.6 0.8 1.2 0.6 0.7 1.4 1.0 0.5 1.1312
mmu-mir-29b-2-3p_-_1 2.5 1.4 1.9 0.7 0.0 1.4 0.7 1.0 2.7518
mmu-mir-29b-1-3p_-_1 2.5 1.4 1.9 0.7 0.0 1.4 0.7 1.0 2.7518
mmu-mir-455-3p_-_1 1.1 1.1 1.1 0.0 2.4 1.4 1.9 0.7 0.6092
mmu-let-7a-1-5p_+_3 1.1 0.9 1.0 0.2 1.0 1.4 1.2 0.3 0.8714
Page 46 of 55
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Diabetes
mmu-mir-669c-5p 0.8 1.0 0.9 0.2 0.8 1.4 1.1 0.4 0.8214
mmu-mir-505-5p 1.1 1.4 1.3 0.2 0.7 1.4 1.0 0.5 1.2558
mmu-mir-27b-5p_-_1 1.1 0.0 0.5 0.8 0.0 1.4 0.7 1.0 0.7859
mmu-mir-191-5p_+_5 0.7 0.0 0.4 0.5 0.0 1.4 0.7 1.0 0.5239
mmu-mir-132-3p_+_1 0.0 0.0 0.0 0.0 0.0 1.4 0.7 1.0 0.0000
mmu-let-7f-2-5p_+_3 1.0 1.1 1.1 0.0 0.0 1.3 0.7 0.9 1.6133
mmu-mir-365-2-5p_-_1 2.4 2.0 2.2 0.3 1.6 1.3 1.5 0.2 1.5011
mmu-mir-676-3p_+_1 0.0 1.2 0.6 0.9 0.9 1.3 1.1 0.3 0.5505
mmu-mir-1948-3p_-_1 1.6 1.7 1.6 0.1 0.8 1.3 1.1 0.3 1.5289
mmu-mir-296-5p 0.0 1.6 0.8 1.1 0.8 1.3 1.0 0.4 0.7541
mmu-mir-672-5p 0.0 0.0 0.0 0.0 0.7 1.3 1.0 0.4 0.0000
mmu-mir-340-5p_-_1 2.2 1.0 1.6 0.8 0.7 1.3 1.0 0.4 1.6140
mmu-mir-22-3p_+_3 1.4 1.3 1.4 0.1 0.0 1.3 0.6 0.9 2.1126
mmu-mir-21-5p_+_5 1.0 0.9 1.0 0.1 0.0 1.3 0.6 0.9 1.5335
mmu-mir-148b-5p_+_1 0.0 0.9 0.5 0.7 0.0 1.3 0.6 0.9 0.7185
mmu-mir-125a-5p_+_4 0.7 0.0 0.4 0.5 0.0 1.3 0.6 0.9 0.5821
mmu-mir-92b-3p_+_1 0.0 0.0 0.0 0.0 0.0 1.3 0.6 0.9 0.0000
mmu-mir-26a-2-5p_+_4 1.6 0.0 0.8 1.1 0.8 1.3 1.0 0.3 0.7891
mmu-mir-26a-1-5p_+_4 1.6 0.0 0.8 1.1 0.8 1.3 1.0 0.3 0.7891
mmu-mir-501-5p 0.0 0.0 0.0 0.0 0.0 1.3 0.6 0.9 0.0000
mmu-mir-187-3p_+_1 0.8 1.0 0.9 0.1 1.1 1.2 1.1 0.1 0.8004
mmu-mir-148a-3p_+_3 3.7 0.0 1.9 2.6 1.1 1.2 1.1 0.1 1.6210
mmu-mir-1934-5p 0.0 1.1 0.5 0.8 0.8 1.2 1.0 0.3 0.5363
mmu-mir-365-2-5p 2.4 1.0 1.7 1.0 0.8 1.2 1.0 0.3 1.7057
mmu-mir-3082-3p_+_2 1.6 0.8 1.2 0.5 0.8 1.2 1.0 0.3 1.1767
mmu-mir-26a-1-5p_+_3 1.6 0.0 0.8 1.1 0.7 1.2 1.0 0.3 0.8303
mmu-mir-26a-2-5p_+_3 1.6 0.0 0.8 1.1 0.7 1.2 1.0 0.3 0.8303
mmu-mir-421-3p_+_4 1.0 0.0 0.5 0.7 0.7 1.2 1.0 0.3 0.5283
mmu-mir-615-3p 0.0 0.0 0.0 0.0 0.7 1.2 1.0 0.3 0.0000
mmu-mir-28-3p_-_1 0.7 0.9 0.8 0.1 0.7 1.2 0.9 0.4 0.8800
mmu-mir-16-2-3p 1.1 2.0 1.5 0.6 0.0 1.2 0.6 0.8 2.5563
mmu-mir-16-1-3p 0.7 1.4 1.0 0.4 0.0 1.2 0.6 0.8 1.7239
mmu-mir-190b-5p 0.8 0.8 0.8 0.0 0.0 1.2 0.6 0.8 1.3500
mmu-mir-32-3p 1.4 0.0 0.7 1.0 0.0 1.2 0.6 0.8 1.1976
mmu-mir-192-5p_+_5 1.1 0.0 0.5 0.8 0.0 1.2 0.6 0.8 0.8982
mmu-mir-200b-3p_+_2 1.0 0.0 0.5 0.7 0.0 1.2 0.6 0.8 0.8483
mmu-let-7e-3p_+_1 0.0 0.0 0.0 0.0 0.0 1.2 0.6 0.8 0.0000
mmu-mir-132-5p 0.0 0.0 0.0 0.0 0.0 1.2 0.6 0.8 0.0000
mmu-mir-425-3p_-_2 0.0 0.0 0.0 0.0 0.0 1.2 0.6 0.8 0.0000
mmu-let-7f-1-5p_+_3 0.9 0.0 0.4 0.6 0.0 1.2 0.6 0.8 0.7394
mmu-mir-21-5p_+_6 1.0 1.2 1.1 0.1 0.0 1.2 0.6 0.8 1.9188
Page 47 of 55
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Diabetes
mmu-let-7d-5p_+_3 0.0 0.0 0.0 0.0 0.0 1.1 0.6 0.8 0.0000
mmu-mir-3107-3p 1.0 2.1 1.6 0.8 1.7 1.1 1.4 0.4 1.1330
mmu-mir-196b-5p 1.3 1.4 1.3 0.1 1.5 1.1 1.3 0.3 0.9920
mmu-mir-1981-3p_+_1 2.2 1.7 1.9 0.3 1.2 1.1 1.2 0.1 1.6602
mmu-let-7b-5p_+_5 0.0 1.2 0.6 0.9 1.1 1.1 1.1 0.0 0.5560
mmu-mir-193b-3p_+_1 0.0 0.0 0.0 0.0 1.0 1.1 1.1 0.1 0.0000
mmu-let-7g-3p_+_1 0.8 1.8 1.3 0.7 0.8 1.1 1.0 0.2 1.3435
mmu-mir-222-3p_-_2 0.0 0.8 0.4 0.6 0.0 1.1 0.6 0.8 0.7015
mmu-mir-30a-5p_+_4 1.1 0.0 0.5 0.8 0.0 1.1 0.6 0.8 0.9673
mmu-mir-26a-2-5p_+_2 1.1 0.0 0.5 0.8 0.0 1.1 0.6 0.8 0.9673
mmu-mir-3060-3p_+_2 1.0 0.0 0.5 0.7 0.0 1.1 0.6 0.8 0.9135
mmu-mir-30a-5p_+_5 1.0 0.0 0.5 0.7 0.0 1.1 0.6 0.8 0.8598
mmu-mir-106a-5p 0.7 0.0 0.4 0.5 0.0 1.1 0.6 0.8 0.6717
mmu-mir-129-1-3p 0.7 0.0 0.4 0.5 0.0 1.1 0.6 0.8 0.6448
mmu-mir-5122_+_8 0.0 0.0 0.0 0.0 0.0 1.1 0.6 0.8 0.0000
mmu-mir-132-3p_+_2 0.0 0.0 0.0 0.0 0.0 1.1 0.6 0.8 0.0000
mmu-mir-122-5p_+_7 1.0 0.9 1.0 0.1 0.7 1.1 0.9 0.3 1.0683
mmu-mir-92a-1-3p_+_4 0.0 0.0 0.0 0.0 0.0 1.1 0.5 0.8 0.0000
mmu-mir-490-3p 0.0 0.0 0.0 0.0 0.0 1.1 0.5 0.8 0.0000
mmu-let-7c-2-5p_+_6 0.8 0.0 0.4 0.6 0.0 1.1 0.5 0.7 0.7741
mmu-let-7c-2-5p_-_1 0.7 0.8 0.8 0.1 0.0 1.0 0.5 0.7 1.4933
mmu-mir-148a-3p_+_5 2.0 0.8 1.4 0.9 0.8 1.0 0.9 0.1 1.5178
mmu-mir-425-5p_+_1 1.1 1.8 1.5 0.5 0.7 1.0 0.9 0.2 1.6665
mmu-mir-16-1-5p_+_1 0.8 1.4 1.1 0.4 0.0 1.0 0.5 0.7 2.0986
mmu-mir-30a-5p_+_7 1.4 1.1 1.3 0.2 0.0 1.0 0.5 0.7 2.4443
mmu-mir-338-5p_-_2 1.5 1.1 1.3 0.3 0.0 1.0 0.5 0.7 2.4917
mmu-mir-301b-3p 0.0 0.8 0.4 0.6 0.0 1.0 0.5 0.7 0.7945
mmu-mir-191-5p_+_2 1.2 0.0 0.6 0.8 0.0 1.0 0.5 0.7 1.1643
mmu-mir-26a-1-5p_+_2 1.1 0.0 0.5 0.8 0.0 1.0 0.5 0.7 1.0479
mmu-mir-592-5p_+_1 1.0 0.0 0.5 0.7 0.0 1.0 0.5 0.7 0.9897
mmu-mir-664-3p_+_2 1.0 0.0 0.5 0.7 0.0 1.0 0.5 0.7 0.9314
mmu-mir-223-3p_-_1 0.8 0.0 0.4 0.6 0.0 1.0 0.5 0.7 0.8150
mmu-mir-326-3p_+_1 0.0 0.0 0.0 0.0 0.0 1.0 0.5 0.7 0.0000
mmu-mir-5122_+_1 0.0 0.0 0.0 0.0 0.0 1.0 0.5 0.7 0.0000
mmu-mir-100-5p_-_1 0.0 0.0 0.0 0.0 0.0 1.0 0.5 0.7 0.0000
mmu-mir-330-3p 0.0 0.0 0.0 0.0 0.0 1.0 0.5 0.7 0.0000
mmu-mir-485-3p_+_1 0.0 0.0 0.0 0.0 0.0 1.0 0.5 0.7 0.0000
mmu-mir-5102_-_4 1.6 1.5 1.5 0.1 6.3 1.0 3.6 3.7 0.4230
mmu-let-7a-1-5p_+_4 0.0 0.0 0.0 0.0 0.0 1.0 0.5 0.7 0.0000
mmu-let-7a-2-5p_+_4 0.0 0.0 0.0 0.0 0.0 1.0 0.5 0.7 0.0000
mmu-let-7f-1-5p_+_6 0.9 0.8 0.8 0.1 0.0 1.0 0.5 0.7 1.7169
Page 48 of 55
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Diabetes
mmu-mir-151-5p_+_1 1.0 1.2 1.1 0.1 0.7 1.0 0.8 0.2 1.3634
mmu-mir-296-3p 0.0 0.0 0.0 0.0 0.0 1.0 0.5 0.7 0.0000
mmu-mir-122-5p_-_2 0.9 0.0 0.4 0.6 0.9 0.9 0.9 0.0 0.4851
mmu-mir-99a-5p_+_5 1.6 0.9 1.3 0.5 0.7 0.9 0.8 0.2 1.5788
mmu-mir-130a-3p_-_1 1.3 1.4 1.3 0.0 0.0 0.9 0.5 0.7 2.8292
mmu-mir-664-5p_+_1 0.9 1.4 1.1 0.3 0.0 0.9 0.5 0.7 2.3846
mmu-mir-16-2-5p_+_1 0.8 1.4 1.1 0.4 0.0 0.9 0.5 0.7 2.2893
mmu-mir-130a-3p_+_4 0.0 1.1 0.6 0.8 0.0 0.9 0.5 0.7 1.2059
mmu-mir-29b-2-5p 0.7 1.1 0.9 0.2 0.0 0.9 0.5 0.7 1.8926
mmu-mir-100-5p_+_4 0.9 0.8 0.8 0.1 0.0 0.9 0.5 0.7 1.7817
mmu-mir-30d-5p_+_2 0.9 0.0 0.5 0.7 0.0 0.9 0.5 0.7 0.9844
mmu-let-7c-1-5p_+_6 0.8 0.0 0.4 0.5 0.0 0.9 0.5 0.7 0.8044
mmu-mir-744-5p_+_1 0.0 0.0 0.0 0.0 0.0 0.9 0.5 0.7 0.0000
mmu-mir-455-3p_-_3 0.0 0.0 0.0 0.0 0.0 0.9 0.5 0.7 0.0000
mmu-mir-221-5p_-_1 0.0 0.0 0.0 0.0 0.0 0.9 0.5 0.7 0.0000
mmu-mir-351-5p_-_1 0.0 0.0 0.0 0.0 0.0 0.9 0.5 0.7 0.0000
mmu-mir-223-5p_-_1 0.0 0.0 0.0 0.0 0.0 0.9 0.5 0.7 0.0000
mmu-mir-5117-3p_-_7 0.0 0.0 0.0 0.0 0.0 0.9 0.5 0.7 0.0000
mmu-mir-218-1-5p 0.0 0.0 0.0 0.0 0.0 0.9 0.5 0.7 0.0000
mmu-mir-382-5p 0.0 0.0 0.0 0.0 0.0 0.9 0.5 0.7 0.0000
mmu-mir-5102_-_8 0.6 0.8 0.7 0.1 4.4 0.9 2.7 2.5 0.2624
mmu-mir-16-2-5p_-_1 0.0 1.4 0.7 1.0 0.0 0.9 0.5 0.6 1.5397
mmu-mir-191-5p_+_7 1.0 1.2 1.1 0.2 0.0 0.9 0.5 0.6 2.4068
mmu-let-7f-2-5p_+_4 1.1 0.9 1.0 0.1 0.0 0.9 0.5 0.6 2.1471
mmu-mir-27a-3p_-_1 0.7 0.0 0.3 0.5 0.0 0.9 0.5 0.6 0.7651
mmu-mir-187-5p_+_2 0.0 0.0 0.0 0.0 0.0 0.9 0.5 0.6 0.0000
mmu-mir-34b-5p 0.0 0.0 0.0 0.0 0.0 0.9 0.5 0.6 0.0000
mmu-let-7g-5p_+_6 0.8 0.0 0.4 0.6 0.0 0.9 0.4 0.6 0.9329
mmu-mir-20b-5p 0.0 0.0 0.0 0.0 0.0 0.9 0.4 0.6 0.0000
mmu-mir-1940 1.0 0.0 0.5 0.7 1.5 0.9 1.2 0.5 0.4052
mmu-let-7f-2-3p 7.0 5.7 6.4 0.9 3.3 0.0 1.7 2.4 3.8095
mmu-mir-5102_-_2 1.0 1.2 1.1 0.1 3.1 0.0 1.6 2.2 0.6846
mmu-mir-5102_-_7 0.7 0.9 0.8 0.2 2.8 0.0 1.4 2.0 0.5912
mmu-mir-486-5p_-_2 1.7 3.8 2.8 1.4 2.5 0.0 1.2 1.8 2.2158
mmu-mir-28c_-_1 3.0 3.1 3.1 0.1 2.4 0.0 1.2 1.7 2.5175
mmu-mir-5102_+_8 0.0 0.0 0.0 0.0 2.0 0.0 1.0 1.4 0.0000
mmu-mir-1247-3p 2.3 0.0 1.1 1.6 1.9 0.0 1.0 1.4 1.1739
mmu-mir-215-3p 14.5 1.2 7.9 9.4 1.8 0.0 0.9 1.2 8.9372
mmu-mir-5126 0.0 0.9 0.4 0.6 1.6 0.0 0.8 1.1 0.5440
mmu-mir-33-3p 2.2 1.1 1.7 0.8 1.6 0.0 0.8 1.1 2.1288
mmu-mir-375-3p_-_1 1.3 0.0 0.6 0.9 1.5 0.0 0.7 1.0 0.8650
Page 49 of 55
For Peer Review Only
Diabetes
mmu-mir-1943-5p 1.0 0.9 0.9 0.1 1.2 0.0 0.6 0.9 1.5442
mmu-mir-1247-5p_-_1 0.8 0.0 0.4 0.6 1.2 0.0 0.6 0.8 0.7284
mmu-mir-486-5p_+_1 0.9 1.6 1.3 0.5 1.1 0.0 0.5 0.8 2.2903
mmu-mir-3107-5p_+_1 0.9 1.6 1.3 0.5 1.0 0.0 0.5 0.7 2.4251
mmu-mir-1843-3p_-_3 0.0 0.0 0.0 0.0 1.0 0.0 0.5 0.7 0.0000
mmu-mir-128-1-5p 0.8 0.9 0.8 0.0 1.0 0.0 0.5 0.7 1.7449
mmu-mir-328-3p_-_1 0.8 0.7 0.8 0.0 1.0 0.0 0.5 0.7 1.5731
mmu-mir-375-3p_+_1 1.0 0.0 0.5 0.7 1.0 0.0 0.5 0.7 0.9886
mmu-mir-3105-5p 0.0 0.0 0.0 0.0 1.0 0.0 0.5 0.7 0.0000
mmu-mir-139-3p_+_3 0.0 0.9 0.4 0.6 0.9 0.0 0.5 0.6 0.9386
mmu-let-7b-5p_-_1 0.0 0.8 0.4 0.6 0.9 0.0 0.5 0.6 0.8604
mmu-mir-5102_+_1 0.8 0.0 0.4 0.6 0.9 0.0 0.5 0.6 0.8568
mmu-mir-1948-5p 1.3 1.2 1.2 0.1 0.9 0.0 0.4 0.6 2.8027
mmu-mir-383-5p 1.7 1.2 1.5 0.4 0.8 0.0 0.4 0.6 3.4724
mmu-mir-5126_+_1 0.0 0.0 0.0 0.0 0.8 0.0 0.4 0.6 0.0000
mmu-mir-1968-5p_-_2 1.4 1.2 1.3 0.1 0.8 0.0 0.4 0.6 3.4044
mmu-mir-351-3p_+_2 0.0 0.0 0.0 0.0 0.8 0.0 0.4 0.6 0.0000
mmu-mir-351-5p_+_1 0.0 0.0 0.0 0.0 0.7 0.0 0.4 0.5 0.0000
mmu-mir-30d-5p_+_6 0.0 0.0 0.0 0.0 0.7 0.0 0.4 0.5 0.0000
mmu-mir-15a-3p 1.0 1.2 1.1 0.1 0.7 0.0 0.3 0.5 3.3409
mmu-mir-486-3p_-_2 0.0 0.9 0.4 0.6 0.7 0.0 0.3 0.5 1.2799
mmu-mir-328-3p_+_1 0.0 0.8 0.4 0.6 0.7 0.0 0.3 0.5 1.1732
mmu-mir-201-5p 1.7 0.0 0.8 1.2 0.7 0.0 0.3 0.5 2.5164
mmu-mir-30c-1-3p_+_1 0.9 0.0 0.4 0.6 0.7 0.0 0.3 0.5 1.3481
mmu-mir-30d-5p_+_5 0.0 0.0 0.0 0.0 0.7 0.0 0.3 0.5 0.0000
mmu-mir-27a-5p 0.0 0.0 0.0 0.0 0.7 0.0 0.3 0.5 0.0000
mmu-mir-144-5p_+_1 1.4 1.7 1.5 0.2 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-29c-3p_+_4 1.3 1.6 1.4 0.3 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-26b-5p_-_1 0.8 1.6 1.2 0.6 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-219-1-5p 0.9 1.5 1.2 0.4 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-1933-3p 1.4 1.2 1.3 0.1 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-16-2-5p_+_5 1.3 1.2 1.3 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-192-5p_-_2 2.0 1.2 1.6 0.6 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-192-3p_-_1 0.0 1.2 0.6 0.9 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-16-1-5p_+_5 1.3 1.2 1.2 0.1 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-3073-3p 0.9 1.1 1.0 0.1 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-802-5p_-_1 2.7 1.0 1.8 1.2 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-16-1-3p_-_1 0.0 1.0 0.5 0.7 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-486-5p_+_3 0.9 1.0 1.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-98-3p 1.5 0.9 1.2 0.4 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-10a-5p_+_5 1.4 0.9 1.2 0.4 0.0 0.0 0.0 0.0 #DIV/0!
Page 50 of 55
For Peer Review Only
Diabetes
mmu-mir-26a-2-5p_-_1 1.2 0.9 1.1 0.2 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-126-5p_-_1 0.0 0.9 0.5 0.7 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-30a-5p_-_1 1.1 0.9 1.0 0.2 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-203-3p_-_1 1.0 0.9 0.9 0.1 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-17-5p_-_1 0.8 0.9 0.8 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-137-3p_+_1 0.8 0.9 0.8 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-295-3p 0.8 0.9 0.8 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-186-5p_-_1 0.0 0.9 0.4 0.6 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-22-3p_+_5 1.0 0.8 0.9 0.1 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-101c_-_2 0.7 0.8 0.7 0.1 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-24-2-3p_+_2 1.0 0.8 0.9 0.2 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-24-1-3p_+_2 1.0 0.8 0.9 0.2 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-374-3p_-_7 1.0 0.8 0.9 0.1 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-98-3p_+_1 0.8 0.8 0.8 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-10a-3p_-_1 0.8 0.8 0.8 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-3107-5p_+_3 0.7 0.8 0.7 0.1 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-126-5p_+_2 3.5 0.0 1.8 2.5 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-194-1-3p 2.3 0.0 1.2 1.7 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-148a-3p_+_7 1.8 0.0 0.9 1.3 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-1843-5p_-_2 1.8 0.0 0.9 1.3 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-126-3p_+_2 1.8 0.0 0.9 1.3 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-203-3p_+_2 1.5 0.0 0.8 1.1 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-3082-3p_-_1 1.4 0.0 0.7 1.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-26b-5p_+_2 1.3 0.0 0.7 0.9 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-126-5p_+_3 1.2 0.0 0.6 0.8 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-505-3p 1.1 0.0 0.5 0.8 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-191-5p_+_3 1.1 0.0 0.5 0.8 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-30c-1-5p_-_1 1.0 0.0 0.5 0.7 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-30c-2-5p_-_1 1.0 0.0 0.5 0.7 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-7a-1-3p_+_1 1.0 0.0 0.5 0.7 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-101b-3p_-_2 1.0 0.0 0.5 0.7 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-27b-3p_+_2 1.0 0.0 0.5 0.7 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-676-5p_+_1 1.0 0.0 0.5 0.7 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-15a-5p_-_1 1.0 0.0 0.5 0.7 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-1960 0.9 0.0 0.4 0.6 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-802-3p_-_1 0.9 0.0 0.4 0.6 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-26b-5p_+_3 0.9 0.0 0.4 0.6 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-1948-5p_-_1 0.9 0.0 0.4 0.6 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-26a-1-5p_-_1 0.9 0.0 0.4 0.6 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-29c-3p_+_2 0.8 0.0 0.4 0.6 0.0 0.0 0.0 0.0 #DIV/0!
mmu-let-7g-5p_+_1 0.8 0.0 0.4 0.6 0.0 0.0 0.0 0.0 #DIV/0!
Page 51 of 55
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Diabetes
mmu-let-7f-1-5p_+_4 0.8 0.0 0.4 0.6 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-192-5p_-_3 0.8 0.0 0.4 0.6 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-26a-1-5p_-_3 0.8 0.0 0.4 0.6 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-203-3p_-_2 0.8 0.0 0.4 0.6 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-28c_-_3 0.8 0.0 0.4 0.6 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-101b-3p_+_4 0.8 0.0 0.4 0.5 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-16-2-5p_+_4 0.7 0.0 0.4 0.5 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-16-1-5p_+_4 0.7 0.0 0.4 0.5 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-107-5p 0.7 0.0 0.4 0.5 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-10a-5p_+_4 0.7 0.0 0.4 0.5 0.0 0.0 0.0 0.0 #DIV/0!
mmu-let-7g-5p_-_2 0.7 0.0 0.4 0.5 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-1843-3p_-_2 0.7 0.0 0.4 0.5 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-1955-3p 0.7 0.0 0.4 0.5 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-30a-5p_+_6 0.7 0.0 0.4 0.5 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-338-3p_+_1 0.7 0.0 0.4 0.5 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-151-5p_-_2 0.7 0.0 0.3 0.5 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-10a-3p_-_2 0.7 0.0 0.3 0.5 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-30d-5p_-_1 0.7 0.0 0.3 0.5 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-29c-5p_+_1 0.7 0.0 0.3 0.5 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-30a-5p_+_3 0.7 0.0 0.3 0.5 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-378b 0.7 0.0 0.3 0.5 0.0 0.0 0.0 0.0 #DIV/0!
mmu-let-7e-5p_-_1 0.6 0.0 0.3 0.5 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-21-5p_+_2 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-155-5p_+_1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-133a-1-3p_+_2 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-let-7c-2-5p_+_2 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-9-2-5p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-3970_-_1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-323-3p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-452-5p_-_3 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-329-5p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-let-7b-5p_+_6 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-504-5p_+_1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-215-5p_+_3 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-668-3p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-1306-3p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-191-5p_-_1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-200b-5p_+_1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-10b-5p_+_4 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-375-3p_+_2 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-760-3p_-_1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
Page 52 of 55
For Peer Review Only
Diabetes
mmu-mir-193b-5p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-let-7a-2-5p_+_1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-181a-1-5p_-_1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-708-5p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-615-5p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-341-3p_-_1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-141-5p_-_1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-3074-1-5p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-133b-3p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-467e-5p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-380-3p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-141-3p_-_1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-377-3p_-_3 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-341-3p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-200b-3p_+_3 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-378-3p_+_5 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-378-3p_-_2 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-409-3p_+_1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-5117-3p_-_8 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-10b-5p_+_2 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-124-3-3p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-181b-1-3p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-10b-5p_-_1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-196a-1-3p_-_1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-let-7d-5p_+_5 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-3058-3p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-1843b-3p_-_4 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-let-7i-5p_+_1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-194-1-3p_+_1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-181a-2-5p_-_1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-124-2-3p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-181c-5p_-_1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-181c-3p_-_1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-5117-5p_-_1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-490-3p_-_1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-205-3p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-145-5p_+_3 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-183-5p_+_7 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-10b-3p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-421-3p_+_3 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-467e-5p_+_1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
Page 53 of 55
For Peer Review Only
Diabetes
mmu-mir-183-3p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-382-5p_+_1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-495-3p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-3074-2-5p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-138-1-5p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-1a-2-3p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-141-5p_-_2 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-490-5p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-let-7c-1-5p_+_2 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-200a-3p_+_1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-20a-3p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-467c-5p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-196a-2-5p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-127-3p_-_2 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-9-3-5p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-667-3p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
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mmu-mir-153-3p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
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mmu-mir-411-3p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-218-1-3p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-1224-5p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-329-3p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-668-3p_-_1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-300-3p_+_4 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-124-1-3p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-23b-5p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-127-5p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-10b-3p_-_1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
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mmu-let-7e-5p_+_5 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-455-5p_-_1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-154-5p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-1983 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-10b-3p_+_1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-369-5p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
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mmu-mir-10a-5p_-_2 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-299-5p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-127-5p_+_2 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
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mmu-mir-708-3p_+_1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
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mmu-mir-147-3p_-_1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
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mmu-mir-218-2-5p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-23a-3p_+_3 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-369-3p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-10b-5p_+_5 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-429-3p_+_1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-215-5p_-_1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-375-5p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
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mmu-mir-200b-3p_-_1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
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mmu-mir-5117-3p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-10b-5p_+_3 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-708-3p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
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mmu-mir-490-3p_-_2 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-200c-5p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
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mmu-mir-7a-2-3p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
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mmu-mir-383-5p_-_1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-376b-5p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-103-2-5p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-370-3p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-125a-5p_+_3 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-376c-3p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
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mmu-mir-141-3p_+_1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
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mmu-mir-136-3p_+_1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-181c-5p_+_1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-196a-2-5p_+_1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-9-1-5p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
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mmu-mir-376b-3p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
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mmu-mir-3074-1-3p 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
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mmu-mir-133a-2-3p_+_2 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
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mmu-mir-1306-3p_-_1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-136-5p_-_3 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
mmu-mir-541-5p_+_1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
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mmu-let-7a-1-5p_+_1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 #DIV/0!
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