Что же такое эпигенетика? Vasily Ogryzko Group of “Proteomics &...

Что же такое эпигенетика?Vasily Ogryzko

Group of “Proteomics & epigenetics’, UMR 8126 CNRS, Institut Gustave Roussy16 мая 2014

Программа визитов иностранных учёных в российские научные центры фонда "Династия"

Importance of proteomics...

… and epigenetics

Epigenetics

Chromatin

Against Central Dogma or not?

Why the definition of epigenetics has changed?

Scope and terminology of epigenetics

Conserved epigenes

Roles of epigenetic information

Epigenetics and evolution

Non-chromatin-based epigenetic mechanisms

Why it is interesting?

Genotype

Phenotype

It seems to go against the grain of the Central Dogma of Molecular Biology

Genocentric view and Central Dogma

Importantly, there is no direct contradiction:

Crick: The central dogma of molecular biology deals with the detailed residue-by-residue transfer of sequential information. It

states that such information cannot be transferred from protein to either protein or nucleic acid.

Phenomenon of iPS cell reprogramming and somatic cloning – genetic information is not sufficient to define the

state of a cell.

‘Genocentric’ view runs into problem when one start to deal with the multicellular organisms exhibiting the

phenomenon of cellular differentiation

This leaves the door open for other types of information that could be required to specify the state of the organism/cell and might propagate independently from the

DNA sequence

Epigenetics

Chromatin




Conserved epigenes




Conrad Waddington Epigenetic landscape

Epigenetics, past and present. I

Emphasis of relative decoupling of development from genes (phenocopies, tolerance to mutations)

Epigenetics - study of how interactions between genes creates stable trajectories of development

Epigenetics, past and present. II

Modern definition - ‘heritable variations in phenotype that cannot be accounted for by variations in DNA sequence’

Canonic models:

Position effect variegation in drosophila

Silencing in yeast

DNA Methylation

Holy grail - stability of differentiated phenotypes in development

The concept of ‘epigenetic inheritance’ acquired meaning, as everything that is heritable, but not reducible to DNA sequence.

But how to describe stability of cell types after differentiation in development (cellular memory)?

Result of a change in meaning of ‘genetic’

Why change in definition of ‘epigenetic’?

After Watson & Crick -Genes DNA (RNA) sequences,

Genetics - science of inheritance

Therefore, ‘epigenetic inheritance’ has no meaning (Oxymoron)

‘All things genetic’ become associated with nucleic acids

Epigenetics

Chromatin




Conserved epigenes




Types of epigenetic phenomena:1. Germ-line epigenetic inheritance

2. Epigenetic inheritance

3. Epigenetic stability

muscle brain

Meiosis

Mitosis, development

No replication,heritability criteria does not apply,but mechanisms the same

Heritability requirement is too restrictive

What is ‘Epigenetic’?

‘Nonmendelian’ requirement is too loose

Plasmids

Viruses

Selfish genetic elements:

Organelle genomes

Mitochondria

Plastids

What is ‘Epigenetic’?

Epigenetic information - information that is necessary to specify the phenotype of an organism in addition to genetic sequence and the state of the environment

Important in:* Development and differentiation

* Cancer and other pathologies* Therapeutic cloning

Phenotype = F(genes, environment)???}+ Epigenetic information!!!

Working definition

Is the notion of ‘epigenetic regulation’ useful or confusing?

Epigenetic regulation (control/circuits etc) - used to be called regulation of gene expression

Genetic Switch was renamed to Epigenetic Switch by Ptashne himself

Phage l system

The value of a scientific concept depends on: (i) how well it can capture a particular class of phenomena by clearly

distinguishing it from other phenomena, (ii) whether it can stimulate new directions of research(iii) whether it allows one to convey complicated ideas in a succinct and lucid fashion.

Insights from ‘epigenetic information’

Genetic Epigenetic

DNA/RNA replication Epigenetic channel

EpigeneGene

Epiallele/EpimutationAllele/Mutation

DNA repair Repair of epigenetic information?

DNA damage response epigenetic damage response?

Epigenetics

Chromatin




Conserved epigenes




Euchromatin

Heterochromatin

Chromatin, the Nature’s Filing Cabinet

Keeping most of the genetic informationarchived, and some accessible for immediate use

Epigenetic marks on chromatin

2. Post-translational histone modifications

3. Chromatin proteins (alternative histones etc)

1. DNA methylation

Active chromatin: H3.3, H2A.BBDSilenced chromatin: macroH2A1,2

Active chromatin: acetylation, H3K4 methylationSilenced chromatin: H3 K9,29 methylation

Epigenetic templating

Recruitment of machinery that deposits a particular epigenetic mark to sites on chromatin that contain the same mark

Examples:

Recruitment of bromodomain containingHAT complexes to acetylated chromatin

Recruitment of chromodomain containingHMT complexes to methylated chromatin

Replication of inactive chromatin state

Chromodomain of HP1 binds methylated K9 of the histone H3. During replication,the HP1/Suv39 complex is recruited tomethylated nucleosome and directs methylationof the newly synthesized nucleosomes

HP1b chromo

H3 K9m

Inactive chromatin

Inactive chromatin

Suv39h

HP1+SuVar

Replication

Methylation of adjacent nucleosome

Propagation of methylated state

Newly synthesizednucleosomes

Parentalnucleosomes

Further classification of

epigenetic mechanisms

Fields of chromatin and epigenetics are

overlapping but not identical

Epigenetics

Chromatin




Conserved epigenes




The chromatin based epigenetic mechanismsare cis-mechanisms, as particular locations of genome are marked

Are there trans-acting epigenetic mechanisms?

Transacting epigenes: prions

The transmission mechanism is similar to epigenetic templating: locally in space and time from one molecule to another

Crick F. Memory and molecular turnover. Nature. 1984

Transacting epigenes: memory

R D

I II III

T

Kandel E. Prion-like mechanisms might explain long term potentiation in neurobiological memory

a b

A

B

A BB A

1 2

Pa Pb

Are there epigenetic mechanisms that are global,

i.e. do not involve templating?

Genetic/Epigenetic switch

System has two alternative phenotypic states: (LOn, ROff) or (LOff, ROn)

Generalization to many genes leads to genetic networks with manyalternative states.

Unlike in the case of templating mechanisms, the information is a global property of the system

Phage l system

Epigenetics

Chromatin




Conserved epigenes




Is all epigenetic informationless stable than genetic information?

All examples of epigenetic information reviewed so far (chromatin, transcriptional switch), are less stable than

genetic information

Thus, epigenetics introduces an hierarchy of stabilities (times) in the description of a biological system

However:

Stability of Epigenetic information

Conserved epigenes 1. Homochirality

Proteins contain only L-aminoacids

Nucleic acids contain only D-sugars

Majority of enzymatic reactions are stereospecific and utilize and/or produce chiral molecules

Reflection of the biosphere in a mirror willneither change processes in it nor the sequences of genomes

Giant mirror experiment

At least one additional bit of information is necessary to specify the chirality of biosphere

Therefore, it is information necessary to specify the state of a living object, its integration into the ‘circle of life’

1. Without the knowledge of chirality, apples from Mars could be dangerous

Chirality

2. It is information that is not contained in the sequence of genome,

Therefore, it is epigenetic information

(if each organism has racemases, need much more: 1 bit per each organism)

Nonlocal character of reproduction

Extremely stable. Unlike other types of epigenetic information, more stable than genetic information

Is not a dynamical variable now, was fixed long time ago

Should be a dynamical variable in description of origin of life

Distinguishing features of chirality as epigenetic information

Chirality

Conserved epigenes 2. Genetic code

?

The nucleotide sequence of aatRNA synthetases is coded in genome, but the protein sequence cannot be deduced without a priory knowledge of the code

Similarly, the correspondence between sound ‘a’ and a letter ‘A’ is not coded in a text

Similarly, the information about the representation of aminoacid (Leu) by a codone (CTG) cannot be transmitted from one generation to another throughDNA alone (aatRNA synthetases should be present)

Conserved epigenes 2. Genetic code

The information about representation of a particular phoneme (A) by an alphabet symbol (a) cannot be transmitted between users (generations etc) through

text alone

General principle of functioning of a semiotic system

Arbitrariness of code -

Epigenetics

Chromatin




Conserved epigenes





1. Proper functioning of genetic information

2. Protection of genetic information

In general as a part of a semiotic system

In development, helping to interpret it

DNA methylation

Restriction endonucleases are a natural part ofthe bacterial defence system

Part of the restr iction/ modif ication system found in manybacteria

These enzymes RESTRICT the ability of foreign DNA (suchas bacteriophage DNA) to infect/ invade the host bacterialcell by cutting it up (degrading it)

The host DNA is MODIFIED by METHYLATION of thesequences these enzymes recognise

o Methyl groups are added to C or A nucleotides inorder to protect the bacterial host DNA f romdegradation by its own enzymes

Maintenance methylation

Only semimethylated bases are coverted into fully methylated

DestructionReplication

Crick F. Memory and molecular turnover. Nature. 1984

Epigenetic Templating

R D

I II III

T

Protection of genetic information:

1.From foreign elements -discrimination between ‘self’

and ‘other’

2. From copying errors - discrimination between ‘old

and ‘new’

Mismatch Repair

Protection of genetic information:

The Mismatch Repair mechanism in bacteria takes advantage of

the difference in kinetics betweenreplication of genetic and epigenetic

information

Epigenetics

Chromatin




Conserved epigenes




Epigenetics and evolutionWhich function of epigenetic information came first?

Interpretation of genetic informationor

Protection of genetic information?

Many epigenetic mechanisms appear to be related to mechanisms of suppression of parasitic genetic elements

Epigenetic machinery was established by Life for ‘genome protection’ purposes first. In the further course of evolution, however, the

mechanisms of processing of epigenetic information - which allow recognition of different epigenetic marks and channeling the signals encoded in these marks along appropriate response pathways - were

recruited for other purposes, such as for stabilizing different alternative states of the same organism.

Epigenetic mechanisms reviewed so far:

Cis-, templating: chromatin-based

Trans-, templating: prions

Trans-, distributed: genetic networks

Conserved: chirality, genetic code

Structural versus dynamic invariants

Covalent bond Conservation of momentum

All epigenetic information discussed so far was stored in molecular structure of some kind

Static versus dynamic epigenetic mechanisms

Living systems as open systems far from equilibrium

Selforganization, Dissipative structures

Could information be stored dynamically?

What about information associated with unequilibrium symmetry breaking?

Convection cells

Dynamic flow organizes system to ensure ‘optimal performance’

Information/order is maintained by constant flow of free energy

Waddington-Schmalhausen

Then

Genetic assimilation

Adaptation on epigeneticlevel first

But how adaptation can happen on epigenetic level?

Via self-organization!

Self-organization and evolution

An attractive aspect of ‘self-organization’ is that it impliesthat organism, as a physical structure, has a possibility to adapt before and independent from natural selection and thus provides an alternative model for natural evolution:

1. Dynamics/function determines structure2. Structure becomes fixed by stabilizing/assimilating selection

Contrary to the neodarwinian model:

1. Structure determines function/dynamics2. In this way structures are tested by natural selection.

Self-organization and evolution

Что же такое эпигенетика? Vasily Ogryzko Group of “Proteomics &...

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