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Чт о же т акое эпигенет ика?
Vasily Ogryzko
Group of “Proteomics & epigenetics’, UMR 8126 CNRS, Institut Gustave Roussy
16 мая 2014
Программа визитов иностранных учёных в российские научные центры фонда "Династия"
Importance of proteomics...
… and epigenetics
Epigenetics
Against Central Dogma or not?
Why the definition of epigenetics has changed?
Scope and terminology of epigenetics
Chromatin
Non-chromatin-based epigenetic mechanisms
Conserved epigenes
Roles of epigenetic information
Epigenetics and evolution
Epigenetics
Against Central Dogma or not?
Why the definition of epigenetics has changed?
Scope and terminology of epigenetics
Chromatin
Non-chromatin-based epigenetic mechanisms
Conserved epigenes
Roles of epigenetic information
Epigenetics and evolution
Why it is interesting?
It seems to go against the grain of the Central Dogma of Molecular Biology
Genotype
Phenotype
Genocentric view and Central Dogma
‘Genocentric’ view runs into problem when one start to deal with the
multicellular organisms exhibiting the phenomenon of cellular
differentiation
Phenomenon of iPS cell reprogramming and somatic cloning – genetic
information is not sufficient to define the state of a cell.
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.
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
Against Central Dogma or not?
Why the definition of epigenetics has changed?
Scope and terminology of epigenetics
Chromatin
Non-chromatin-based epigenetic mechanisms
Conserved epigenes
Roles of epigenetic information
Epigenetics and evolution
Epigenetics, past and present. I
Conrad Waddington
Epigenetic landscape
Epigenetics - study of how interactions between genes creates
stable trajectories of development
Emphasis of relative decoupling of development from genes
(phenocopies, tolerance to mutations)
Epigenetics, past and present. II
Modern definition - ‘heritable variations in phenotype that
cannot be accounted for by variations in DNA sequence’
Holy grail - stability of differentiated phenotypes in
development
Canonic models:
Position effect variegation in
drosophila
Silencing in yeast
DNA Methylation
Why change in definition of ‘epigenetic’?
Result of a change in meaning of ‘genetic’
Genetics - science of inheritance
Therefore, ‘epigenetic inheritance’ has no meaning (Oxymoron)
After Watson & Crick Genes  DNA (RNA) sequences,
‘All things genetic’ become associated with nucleic acids
But how to describe stability of cell types after differentiation
in development (cellular memory)?
The concept of ‘epigenetic inheritance’ acquired meaning, as
everything that is heritable, but not reducible to DNA sequence.
Epigenetics
Against Central Dogma or not?
Why the definition of epigenetics has changed?
Scope and terminology of epigenetics
Chromatin
Non-chromatin-based epigenetic mechanisms
Conserved epigenes
Roles of epigenetic information
Epigenetics and evolution
What is ‘Epigenetic’?
Heritability requirement is too restrictive
Types of epigenetic phenomena:
1. Germ-line epigenetic inheritance
Meiosis
2. Epigenetic inheritance
Mitosis, development
3. Epigenetic stability
No replication,heritability
criteria does not apply,
but mechanisms the same
muscle
brain
What is ‘Epigenetic’?
‘Nonmendelian’ requirement is too loose
Selfish genetic elements:
Plasmids
Viruses
Organelle genomes
Mitochondria
Plastids
Working definition
Epigenetic information - information that is necessary
to specify the phenotype of an organism in addition to genetic
sequence and the state of the environment
Phenotype = F(genes, environment)???
}
+ Epigenetic information!!!
Important in:
* Development and differentiation
* Cancer and other pathologies
* Therapeutic cloning
Is the notion of ‘epigenetic regulation’ useful or confusing?
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.
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
Insights from ‘epigenetic information’
Genetic
Epigenetic
DNA/RNA replication
Epigenetic channel
Gene
Epigene
Allele/Mutation
Epiallele/Epimutation
DNA repair
Repair of epigenetic information?
DNA damage response
epigenetic damage response?
Epigenetics
Against Central Dogma or not?
Why the definition of epigenetics has changed?
Scope and terminology of epigenetics
Chromatin
Non-chromatin-based epigenetic mechanisms
Conserved epigenes
Roles of epigenetic information
Epigenetics and evolution
Chromatin, the Nature’s Filing Cabinet
Keeping most of the
genetic information
archived, and some
accessible for
immediate use
Euchromatin
Hetero
chromatin
Epigenetic marks on chromatin
1. DNA methylation
2. Post-translational histone modifications
Active chromatin: acetylation, H3K4 methylation
Silenced chromatin: H3 K9,29 methylation
3. Chromatin proteins (alternative histones etc)
Active chromatin: H3.3, H2A.BBD
Silenced chromatin: macroH2A1,2
Epigenetic templating
Recruitment of machinery that deposits
a particular epigenetic mark to sites on
chromatin that contain the same mark
Examples:
Recruitment of bromodomain containing
HAT complexes to acetylated chromatin
Recruitment of chromodomain containing
HMT complexes to methylated chromatin
Replication of inactive chromatin state
Suv39h
H3 K9m
Inactive chromatin
HP1b chromo
Chromodomain of HP1 binds methylated
K9 of the histone H3. During replication,
the HP1/Suv39 complex is recruited to
methylated nucleosome and directs methylation
of the newly synthesized nucleosomes
Inactive chromatin
HP1+SuVar
Methylation of
adjacent nucleosome
Propagation of
methylated state
Replication
Newly synthesized
nucleosomes
Parental
nucleosomes
Fields of chromatin and
epigenetics are overlapping but
not identical
Further classification
of
epigenetic mechanisms
Epigenetics
Against Central Dogma or not?
Why the definition of epigenetics has changed?
Scope and terminology of epigenetics
Chromatin
Non-chromatin-based epigenetic mechanisms
Conserved epigenes
Roles of epigenetic information
Epigenetics and evolution
The chromatin based epigenetic mechanisms
are 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
Transacting epigenes: memory
Kandel E. Prion-like mechanisms might explain long term
potentiation in neurobiological memory
R
D
T
I
II
III
Crick F. Memory and molecular turnover. Nature. 1984
Are there epigenetic mechanisms that are global,
i.e. do not involve templating?
A
a
A
1
Pb
Pa
B
B
b
A
B
2
Genetic/Epigenetic switch
Phage l system
System has two alternative phenotypic states: (LOn, ROff) or (LOff, ROn)
Generalization to many genes leads to genetic networks with many
alternative states.
Unlike in the case of templating mechanisms,
the information is a global property of the system
Epigenetics
Against Central Dogma or not?
Why the definition of epigenetics has changed?
Scope and terminology of epigenetics
Chromatin
Non-chromatin-based epigenetic mechanisms
Conserved epigenes
Roles of epigenetic information
Epigenetics and evolution
Stability of Epigenetic 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:
Is all epigenetic information
less stable than genetic 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
Giant mirror experiment
Reflection of the biosphere in a mirror will
neither change processes in it nor the sequences of genomes
Chirality
1. Without the knowledge of chirality, apples from Mars could be
dangerous
Therefore, it is information necessary to specify the state of a
living object, its integration into the ‘circle of life’
2. It is information that is not contained in the sequence of genome,
At least one additional bit of information is necessary to
specify the chirality of biosphere
(if each organism has racemases, need much more: 1 bit per each organism)
Therefore, it is epigenetic information
Chirality
Distinguishing features of chirality as epigenetic information
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
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
Conserved epigenes 2. Genetic code
Arbitrariness of code General principle of functioning of a semiotic system
The information about representation of a particular
phoneme (A) by an alphabet symbol (a) cannot be
transmitted between users (generations etc) through
text alone
Similarly, the information about the representation
of aminoacid (Leu) by a codone (CTG) cannot be
transmitted from one generation to another through
DNA alone (aatRNA synthetases should be present)
Epigenetics
Against Central Dogma or not?
Why the definition of epigenetics has changed?
Scope and terminology of epigenetics
Chromatin
Non-chromatin-based epigenetic mechanisms
Conserved epigenes
Roles of epigenetic information
Epigenetics and evolution
Roles of epigenetic information
1. Proper functioning of genetic information
In general as a part of a semiotic system
In development, helping to interpret it
2. Protection of genetic information
Roles of epigenetic information
1. Proper functioning of genetic information
In general as a part of a semiotic system
In development, helping to interpret it
2. Protection of genetic information
DNA methylation
Restriction endonucleases are a natural part of
the bacterial defence system



Part of the restriction/modification system found in many
bacteria
These enzymes RESTRICT the ability of foreign DNA (such
as bacteriophage DNA) to infect/invade the host bacterial
cell by cutting it up (degrading it)
The host DNA is MODIFIED by METHYLATION of the
sequences these enzymes recognise
o Methyl groups are added to C or A nucleotides in
order to protect the bacterial host DNA from
degradation by its own enzymes
Maintenance methylation
Only semimethylated bases
are coverted into fully methylated
Replication
Destruction
Epigenetic Templating
D
R
T
I
II
Crick F. Memory and molecular turnover. Nature. 1984
III
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 between
replication of genetic and epigenetic
information
Epigenetics
Against Central Dogma or not?
Why the definition of epigenetics has changed?
Scope and terminology of epigenetics
Chromatin
Non-chromatin-based epigenetic mechanisms
Conserved epigenes
Roles of epigenetic information
Epigenetics and evolution
Epigenetics and evolution
Epigenetics and evolution
Which function of epigenetic information came first?
Interpretation of genetic information
or
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.
Epigenetics and evolution
Epigenetic mechanisms reviewed so far:
Cis-, templating:
chromatin-based
Trans-, templating: prions
Trans-, distributed: genetic networks
Conserved: chirality, genetic code
All epigenetic information discussed so far was stored in
molecular structure of some kind
Structural versus dynamic invariants
Covalent bond
Conservation of momentum
Static versus dynamic epigenetic mechanisms
Could information be stored dynamically?
What about information associated with unequilibrium
symmetry breaking?
Living systems as open systems far from equilibrium
Selforganization, Dissipative structures
Convection cells
Dynamic flow organizes system
to ensure ‘optimal performance’
Information/order is maintained
by constant flow of free energy
Self-organization and evolution
Waddington-Schmalhausen
Adaptation on epigenetic
level first
Then
Genetic assimilation
But how adaptation can happen on
epigenetic level?
Via self-organization!
Self-organization and evolution
An attractive aspect of ‘self-organization’ is that it implies
that 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 structure
2. Structure becomes fixed by stabilizing/assimilating
selection
Contrary to the neodarwinian model:
1. Structure determines function/dynamics
2. In this way structures are tested by natural selection.