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Epigenetic footprint of obesity and diabetes Francisco Verdeguer, PhD Assistant Professor. Department of Molecular Mechanisms of Disease, University of Zurich.

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Page 1: Epigenetic footprint of obesity and diabetes50625d26-7c71-42da... · Epigenetic footprint of obesity and diabetes Francisco Verdeguer, PhD Assistant Professor. ... mitotically and/or

Epigenetic footprint of obesity and diabetes

Francisco Verdeguer, PhDAssistant Professor. Department of Molecular Mechanisms of Disease, University of Zurich.

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“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?

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50nm

Chromatin fiber “Beads on a string”

Structural organization of the genetic information in the nucleus

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Verdin et al. 2015

Acetylation of histones leads to “open” chromatin conformation

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The histone code: chemical modifications

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Chromatin and gene expression regulation in metabolic disorders

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Chromatin and gene expression regulation in metabolic disorders

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Epigenetic modifications dynamics

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Metabolic regulation by Histone Deacetylases (HDACs)

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Example of histone demethylase in obesity

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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

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MITOCHONDRIAL FUNCTION AND

EPIGENETIC REGULATION

Matilainen et. al, 2017

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Metabolites influence epigenetic dependent control of brown fat differentiation

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Inactivity impairs glucose tolerance via epigenetic mechanisms in skeletal muscle

Kirner et al. 2013

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DNA methylation and exercise

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Dutch “Hunger winter” (1944-1945)

Poor nutrition of pregnant

mothers

Increased fat mass

Diabetes

Hypertension

Psychiatric disorders

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Sales et al. Cell Metabolism 2017

Transgenerational epigenetics

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Epigenetics and metformin

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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

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HIGH FAT DIET – COLD EXPOSURE

Cellular membrane

UCP1, OXPHOS GENES

YY1

BMP8b and GDF15

YY1

X

CHROMATIN REGULATION

ACTIVATOR REPRESSOR

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Sambeat et al. 2017

Insulin sensitivity

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Etchgaray et. al, 2016

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*lifestyle change:• 7% weight loss• 150min exercise/week

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