s stical physics aproach to posttranscriptional …...1. mirna-mediated cerna effect may act as a...
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Statistical Physics Approach to Post-Transcriptional Regulation
Candidate: Araks Martirosyan
Advisors: Andrea De Martino, Enzo Marinari
Collaborator: Matteo Figliuzzi
Rome, 2015
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Introduction
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Gene Expression DNA
Protein [1]
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Gene Expression
RNA
Transcription
DNA
Protein
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Gene Expression
RNA mRNA
ncRNA
Transcription
DNA
Protein
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Gene Expression
RNA mRNA
ncRNA
TranscriptionTranslation
DNA
Protein
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ncRNA
RNA mRNA
ncRNA
Constituent RNA
tRNArRNA
...
TranscriptionTranslation
DNA
Protein [2]
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ncRNA
RNA mRNA
ncRNA Regulatory RNA
Constituent RNA
tRNArRNA
...piRNA
siRNA
…
TranscriptionTranslation
DNA
Protein
miRNA
[3,4]
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miRNA
RNA mRNA
ncRNA Regulatory RNA
Constituent RNA
tRNArRNA
...piRNA
siRNA
…
TranscriptionTranslation
DNA
Protein
miRNA
[5]
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miRNA binding
3’UTR ACGACGUUCUCAUUCAGUGGUU 5’ UTR
5’UTR AAUCGCGAAGAUCUACUAGAGUAGGUCACCAGGA 3’ UTR}
}
seed
canonical sitesmRNA
miRNA28
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mRNA cleavage
3’UTR ACGACGUUCUCAUUCAGUGGUU 5’ UTR
5’UTR AAUCGCGAAGAUCUACUAGAGUAGGUCACCAGGA 3’ UTR
5'UTR AAUCGCGAAGAUCUACUAGAGUAGGUCACCAGGA 3'UTR
cleavage
3’UTR ACGACGUUCUCAUUCAGUGGUU 5’ UTR
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Translational repression
3’UTR ACGACGUUCUCAUUCAAUGUUU 5’ UTR
5’UTR AAUCGCGAAGAUCUACUAGAGUAGGUCACCAGGA 3’ UTR
Translational repression
3’UTR ACGACGUUCUCAUUCAAUGUUU 5’ UTR
5’UTR AAUCGCGAAGAUCUACUAGAGUAGGUCACCAGGA 3’ UTR
Ribosome
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miRNA-Target interaction networks
* TargetScan* miRanda
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Competing endogenous RNAs (ceRNAs)
ceRNA2
ceRNA1
miRNA
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ceRNA effect
ceRNA2
ceRNA1
miRNA
[6]
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DebateDenzler et al. (2014)
Mouse hepatocytes
Modulation of miRNA target abundance is unlikely to cause significant effects on gene expression through a ceRNA effect.
Bosson et al. (2014)
mouse embryonic stem cell
miRNA-target pool ratios and an affinity partitioned target pool accurately predict miRNA susceptibility to target competition.
[7, 8]
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The goal
1. Quantify the maximal post-transcriptional regulatory power achievable by miRNA-mediated cross-talk,
2. Explore how heterogeneities in binding affinities influence the latter,
3. Compare the effectiveness miRNA-mediated control with other regulatory elements.
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The model
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ceRNA Network
miRNAceRNA1 ceRNA2
[9, 10]
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ceRNA Network: target binding/unbinding
miRNAceRNA1 ceRNA2
C1 C2
+/- +/-k1
+ k1− k2
−k2
+
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ceRNA Network: ceRNA cleavage
miRNAceRNA1 ceRNA2
C1 C2
+/- +/-k1
+ k1− k2
−k2
+
κ1 κ2
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ceRNA Network: transcription
TF1
n1 miRNAceRNA1
TF2
nµ ceRNA2 n2
TFµ
C1 C2
+/- +/-
k ink ink in kout kout kout
b1 b2β
k1+ k1
− k2−
k2+
κ1 κ2
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ceRNA Network: degradation
TF1
n1 miRNAceRNA1
TF2
nµ ceRNA2 n2
TFµ
C1 C2
+/- +/-
Ø
Ø
Ø
Ø
Øk ink ink in kout kout kout
b1 b2β
σ1 σ2
d2d1k1
+ k1− k2
−k2
+
κ1 κ2
δ
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Dynamics ∂mi∂ t
=bini−d imi−k i+miμ+k i
− c i+ξmi−ξ++ξ−
∂μ∂ t
=βnμ−δμ−k i+miμ+(k i
−+κi)ci+ξμ−ξ++ξ−+ξκ
∂ ci∂ t
=−σimi+∑ik i
+miμ−∑i(k i
−+κi)c i+ξci+ξ+−ξ−−ξκ
∂ni ,μ∂ t
=k in f i ,μh (1−ni ,μ)−kout ni ,μ+ξni ,μ
ceRNA
miRNA
complex
TF binding site occupancy
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Dynamics ∂mi∂ t
=bini−d imi−k i+miμ+k i
− c i+ξmi−ξ++ξ−
∂μ∂ t
=βnμ−δμ−k i+miμ+(k i
−+κi)ci+ξμ−ξ++ξ−+ξκ
∂ ci∂ t
=−σimi+∑ik i
+miμ−∑i(k i
−+κi)c i+ξci+ξ+−ξ−−ξκ
∂ni ,μ∂ t
=k in f i ,μh (1−ni ,μ)−kout ni ,μ+ξni ,μ
n̄i ,μ=k in f i ,μ
h
k in f i ,μh +kout
n̄i ,μ
f i ,μ
fast[11]
1
o
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White noise
<ξ+ (t )ξ+ (t ' )>=k i+ m̄iμ̄ δ(t−t ' ) ,
<ξ−(t )ξ−(t ' )>=k i− c̄iδ(t−t ' ) ,
<ξκ(t )ξκ(t ')>=κi c̄ iδ(t−t ') ,<ξμ (t )ξμ(t ' )>=(β n̄μ+δμ̄)δ(t−t ' ),<ξmi(t )ξmi(t ' )>=(bi n̄i+d i m̄i)δ(t−t ' ) ,
m̄i=bi n̄i+k i
− c̄id i+ki
+ μ̄, μ̄=
β n̄μ+∑i(k i
−+κi) c̄iδ+∑i
k i+ m̄i
, c̄i=k i
+ μ̄ m̄iσi+k i
−+κi.
where
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The method
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Mutual Information
Channel
I ( f j ,m2)=∫df jdm2 p(f j ,m2) log2p(f j ,m2)p(f j) p(m2)
I opt=max p(f j) I (f j ,m2)
[12]
Channel Capacity
f jm2
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Noise and information transmission
I opt=0
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Noise and information transmission
I opt∼0
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Noise and information transmission
I opt=log21√2π e ∫df j 1/σ f j
Popt (f j)=1Z1σ f j
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Channels
TF1
miRNAceRNA ceRNA2 ceRNA2
TF2
ITF
miRNAceRNA
TF1 TFμTF2TFμ ImiRNA
miRNA-channel TF-channel
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Results
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The capacity of the miRNA-channel is maximal in a specific range of miRNA-ceRNA binding rates
ITF - ImiRNATF1
miRNAceRNA ceRNA2 ceRNA2
TF2
miRNAceRNA
ImiRNA ITF
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miRNA-mediated regulation may represent the sole control mechanism in case of differential complex processing
TF1
miRNAceRNA ceRNA2 ceRNA2
TF2
miRNAceRNA
ITF - ImiRNAImiRNA ITF
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Dependence on ∆
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Dependence on ∆
∆σm2
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The limit of weakly interacting high miRNA population
miRNAceRNA2miRNA
ω
ceRNA2ceRNA2ceRNA2k i+→k i
+ ω ,δ→δω .
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Conclusions1. miRNA-mediated ceRNA effect may act as a master regulator of gene expression in the presence of the heterogeneity in target binding affinities, that is the case “in vivo” (Breda et al, 2015 [15]).
miR
NA
The density of target sites
energy of interaction between the miRNA and the target
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Conclusions2. Target derepression may be significant even if the competitor is in low copy numbers, provided a certain heterogeneity in kinetic parameters (e.g. for a catalytically degraded target and a stoichiometrically degraded competitor) is present.
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Thank you!
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