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

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**

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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