le paysage épigénétique… et le hasard jonathan weitzman · croissance et la multiplication de...

Le paysage épigénétique…et le hasard

Jonathan Weitzman

Le hasard, le calcul et la vieCerisy 2019

Monod

« Les êtres vivants sont des machines chimiques. La croissance et la multiplication de tous les organismes exigent que soient accomplies des milliers de réactions chimiques grâce à quoi sont élaborés les constituants essentiels des cellules. »

Monod

« .. the ‘dream’ (as François Jacob has put it) of every cell: to become two cells. »

Epigenetics is being heralded as a scientific revolution

1940s-50s

The century of the gene

1866 1905 1911 1944 1953 1953

1970

Watson Crick

Protein

RNA

DNA

Phenotype

ProteinRNA

Gene

central dogma of molecular biology

Human Genome Project2001

3000 000 000 nucléotides

2,7 $ milliards

« The Book of Life »

3 000 000 000 lettres

a g c t

the human genome

2 997 000 000

a g c t

3 000 000

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personalized genomics

Monod

« Tout ce qui est vrai pour la bactérie Escher ichia coli est vrai pour l’éléphant. »

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There are numerous examples of different phenotypes with the same genotype

divisionfusion jumeaux

du hasard?

Which professor Weitzman…?

1940s-50s

Advances in epigenetics research have paralleled genetics

1866 1953 1970

2012

2001

Waddington

“But between genotype and

phenotype lies a whole complex of

development processes”

Conrad Hal Waddington1905 –1975

epigenetics is ''the branch of biology which studies the causal interactions between genes and their products which bring the phenotype into being.''

Waddington coined the term epigenetics in the 1940s

the theory that embryonic development is due to a series of causal interactions between the various parts; the development of individual

organic form from the unformed Aristotle, 4th Century BCE

Embryogenesis is an increase in size of preformed structures already present in egg … or even in the sperm.«  Homunculus »

epigenesis preformation

epigenetic processes: « As is a crystal, the structure of the assembled molecules itself constitutes the source of ‘information’ for the construction of the whole. »

« This analysis plainly reduces the old dispute between preformationists and epigeneticists to a quibble over words… The necessary information was present, but unexpresssed, in the constituents. The epigenetic building of a structure is not a creation; it is a revelation. »

1959

Waddington introduced the metaphor of the epigenetic landscape

Waddington himself was vague about theepigenetic landscape metaphor

1959

« Although the epigenetic landscape only provides a rough and ready

picture of the developing embryo, and cannot be interpreted rigorously, it has

certain merits for those who, like myself, find it comforting to have some

mental picture, however vague, for what they are trying to think about »

Nanney’s epigenetic control systems

PNAS 1958"Cellular memory"

The definition is constantly evolving

Robin Holliday1932 –2014

epigenetics is ‘the study of the changes in gene expression which occur in organisms with differentiated cells and the mitotic inheritance of given patterns of gene expression.'‘

Somatically heritable though cellular division

1959

Waddington introduced the metaphor of the epigenetic landscape

1959

Waddington speculated about the mechanisms underlying the epigenetic landscape

What’s in the epigenetic toolbox?

Cytosine 5methyl-Cytosine

DNA methylation is an epigenetic mark

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DNA methylation contributes to phenotypic variation

How to bee-come a Queen

Génétique Epi-génétique ?

How to bee-come a Queen

Waterland & Jirtle 2003

Nutritional supplements can impact DNA methylation and phenotypes (vitamin B12/Folate)

The availability of dietary methyl donors affects methylation of the yellow agouti locus

you are what you eat

Proc Natl Acad Sci U S A. 2005

Twin studies reveal that the environment may impact our epigenome throughout life

Genome 2m DNA

Nucleus5μm diameter

15000 km spaghetti Basket ball

Nucleosomes allow 10,000-fold compaction of DNA

euchromatin heterochromatin

ouvertaccessible

ferméeinaccessible

Epigenetic mechanisms control genome functionality

chromatin changes during the lifetime of MZ twins

Histone H4acetylation

Histone H3acetylation

Histone acetylation changes over one’s lifetime

The epigenome as a readout of metabolism

Acetyl coA

S adenosyl Methionine (SAM)

ATP

Environmental influences may be prenatal or postnatal

Encyclopedia of DNA Elements (ENCODE)Nature : 6 september 2012

le paysage épigénétiqueAny position on the epigenetic landscape can be described in terms of epigenome characteristics

We are learning to manipulate the epigenetic landscape

Tomorrow we will use epigenetic knowledge to treat disease

Image courtesy of Shutterstock

Nature vs Nurture

Hasard génétique Hasard epigénétique

Le paysage épigénétique…et le hasard

Jonathan Weitzman

Le hasard, le calcul et la vieCerisy 2019