epigenetic footprint of obesity and diabetes50625d26-7c71-42da... · epigenetic footprint of...
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Epigenetic footprint of obesity and diabetes
Francisco Verdeguer, PhDAssistant Professor. Department of Molecular Mechanisms of Disease, University of Zurich.
“the study of changes in gene function mitotically and/or meiotically heritable and that do not entail a change in DNA sequence”
“the branch of biology which studies the causal interactions between genes andtheir products, which bring the phenotype into being” (Waddington, 1942)
WHAT IS EPIGENETICS?
50nm
Chromatin fiber “Beads on a string”
Structural organization of the genetic information in the nucleus
Verdin et al. 2015
Acetylation of histones leads to “open” chromatin conformation
The histone code: chemical modifications
Chromatin and gene expression regulation in metabolic disorders
Chromatin and gene expression regulation in metabolic disorders
Epigenetic modifications dynamics
Metabolic regulation by Histone Deacetylases (HDACs)
Example of histone demethylase in obesity
HATs
Acetyl-CoA NAD+ a-KG a-KG SAM SAM ATP ADP-Ribose
SIRTs JMJDs TETs HMTs DNMTs Kinases
Histone Acetylation
Histone Deacetylation
Histone demethylation
DNAdemethylation
Histonemethylation
DNAmethylation
PARPs
Histone Phosphorylation
Histone PARylation
CHROMATIN MODIFICATION
EPIGENETIC MAINTENANCE STATES?
Metabolic gene
regulationMe Me
Me MeAc Ac Me Me
Me
PHENOTYPE
Interaction between metabolism and epigenetics
MITOCHONDRIAL FUNCTION AND
EPIGENETIC REGULATION
Matilainen et. al, 2017
Metabolites influence epigenetic dependent control of brown fat differentiation
Inactivity impairs glucose tolerance via epigenetic mechanisms in skeletal muscle
Kirner et al. 2013
DNA methylation and exercise
Dutch “Hunger winter” (1944-1945)
Poor nutrition of pregnant
mothers
Increased fat mass
Diabetes
Hypertension
Psychiatric disorders
Sales et al. Cell Metabolism 2017
Transgenerational epigenetics
Epigenetics and metformin
Control YY1aKO
Total Body Weight
0 2 4 6 8 10
10
20
30
40
50
Weeks on HFD
gra
ms
Control
YY1aKO
*
** *
**
0 1 2 3 4 5 6 7 8 9 10 11 12
10
20
30
40
50
Weeks on HFD
gra
ms
Total Body Weight
Control
YY1bKO
* ** *
* * *B
Yin Yang1 deficiency in adipose tissue protects against diet-induced obesity
HIGH FAT DIET – COLD EXPOSURE
Cellular membrane
UCP1, OXPHOS GENES
YY1
BMP8b and GDF15
YY1
X
CHROMATIN REGULATION
ACTIVATOR REPRESSOR
Sambeat et al. 2017
Insulin sensitivity
Etchgaray et. al, 2016
*lifestyle change:• 7% weight loss• 150min exercise/week
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