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L16 - Epigenetics I Define “epigenetics” Understand that epigenetic…
L16 - Epigenetics I
Define “epigenetics”
Understand that epigenetic marks are inherited and may be influenced by environmental factors
Be able to describe the factors that influence the chromatin structure
Be able to describe the histone code
Describe the different histone modifications and their influence on gene expression
Be able to describe the impact of histone acetylation on gene expression*
Epigenetics - Fundamentlal
Epigenetics
Factors that cause
stable & heritable
, yet
reversible
,
changes
in he way that genes are expressed
without changing
the original DNA sequence
Epigenome - the summation of all the epigenetic tags acting on an individual's genome
Epigenetic Alterations
Achieved by
adding or subtracting
chemical tags
to DNA
Phosphorylation
DNA Methylation
Histone Modification (Acetylation)
“the structural adaptation of chromosomal
regions so as to register, signal or perpetuate altered activity states”
-
Adrian Bird
Epigenetic Inheritance
Some Epigenetic tags are
transferred across generations
During fertilisation, many epigenetic tags are
removed
from the parental chromosomes, yet many remain and can be
transferred to progeny cells
and eventually to subsequent generations of children
Identical Twins
Evidence that epigenetic tags are transferred during fusion of haploid gametes is found in the early similiarities between
identical twins
Yet also evidence that epigenetic tags acquired independently later in life are associated with specific phenotypic expressions
1.
E.g. Fertilistion - Monozygotic twins
Monozygotic twins begin life with the same genetic information, including epigenetic tags
Over time the twins’
environments will diverge
, resulting in individual epigenetic tags to form for each twin.*
The epigenetic tags that each twin acquires in their separate lives could
theoretically have an effect that heightens disease risk
in one twin
3 yo Twins Chr 12s
50 yo Twins Chr 12s
Visibile differences in hyper/hypo - methylation evenets
E.g. Worker or Queen Bee
Honeybees develomental decision to become either a queen or worker is influenced by epigenetic factors -
the type of honey they are fed
Royal vs Common Honey
Determination of honeybee phenotype influecned by epigenetic changes in DNA methylation patterns induced by the different type of honey
1.
Royal jelly
acts on a key gene
(Dnmt3)
which codes for an enzyme that influences
“queen genes
Royal jelly turns Dnmt3 “
off
”, allowing the larvae to develop into a queen as other genes are activated;
larvae => queen bees.
When Dnmt3 is “
on
”, the queen genes
are silenced
; larvae => default “worker”
bees
Royal Honey
Workers Honey
Altering Chromatin Structure
At least three different processes can alter gene
transcription
through chromatin modification
Modification of
histone proteins
Chromatin Remodelling
DNA methylation
These alterations consitute the epigenetic marks that are different throughout the genome
Histone
Histone octamer, when wrapped around by DNA (147bp) and bound by H1 =
Nucleosome
Nucleosomes have N-terminal histone tail -
protrudes
out of the core complex and is the site of many post-transnational modifications
Histone Modification (code)
Pattern of histone modification determine how the histone behaves and may be read as a code
It has information content, which alters the biochemical interaction between the histone complexes and TFs
Modification of the tails act as epigeneitc marks => control expression of chromosomal regions
Phosphate
Methyl
Acetyl
Epigentic marks are heritable - Heritable across cellular division (See slide)
Enzymes (reader write complexes) responsible for implementing histone modifcations, will then re-estabilish the "histone code"by reading modifications inherited and applying themse same mdifications to newly synthesised hstones
Ubiquitin
Active and Repressive Marks
Different amino acids
constituting histone tails receive different covalent modification
specific of each residue
Different covalent modification
specific of each residue, derermines active or repress
Active
Expanded Chromatin
Histone Acetylation
Acetylation occurs on Lysine residues (+ve)
This reduces thei positive charges of histones and diminishes their affinity for DNA
Acteylation
decondenses
chromatin
Deacetylated Lysine residues
Transcription Repression
Histone Deactylase =. HYPOacteylation
Acetylated Lysine Residues
Trancscription activation
Histone Acetykase => HYPERacetylations
DNA De-Methylation
Ten-eleven translocation (TET) family of 5mC hydroxylases include
TET1, TET2 & TET3
Promote DNA demethylation by binding to
CpG rich
regions to prevent unwanted DNA
methyltransferase activity,
and by converting via
hydroxylase activity
;
5mC => 5hmC
5hmC => 5-fc
3.
5-fc => 5caC
TET proteins function
Trascriptional activation and repression
Tumour suppressors
DNA methylation reprogramming (process which requies the TET proteins)
Methylation of Histones
H3K9me3 (Tri-methylase), H3K9me2(Di-methylation
These enzymes methylate Hstones
H3K9me3 recruits HP1
H3K9 & HP1 are important for compacting the chromatin
Repressive
Condensed Chromatn
DNA Methylation
In vertebrates,
5MC residues
within the
CpG
dinucleotide
are most commonly methylated
(methylating systems are unique to specific organisms)
Plants have different methylation (
CpG, CpNpG and CpHpH (H = A, T or C)
) [Plants need to repress their larger genome more effectively??]
DNA Methylation of GC Island
Most genes have GC rich areas in DNA promoter regions =>
CpG islands
Gene Repression = Methylation of
C residues
within the CpG islands
Covalent addition of a methyl group at the 5-carbon of the cytosine ring =
5-methylcytosine (5mC
)
Methyl groups
project into the major
groove of DNA and inhibit transcription
Essential for normal Control of Genome expressio
Active methylases (Reader-writer complex enzymes)
3 DNMTs required for establishment & maintenance of methylation
patterns:
DNMT1, DNMT3a & DNMT3b
2 DNMTs may have
more specialised
but related functions:
DNMT2 and DNMT3L
DMT1
Responsible for maintenance of established patterns of DNA methylation
Fllows the replication fork and methylates newly synthesised DNA
DNMT3a/3b
Mediate establishment De Novo methylation patterns
DNMT3b
May be involved in maintaining hypermethylation in diseased (cancer) cells
CpG Methylation may lead to mutations
5mC is susceptible to transition substitution into Thymine
Changes in Methylation during Development.
Sperm develops slightly different epigenetic marks to the egg
Paternal genome is demethylated more rapidly than the maternal genome, yet they both stabilise at the same level of methylation (
different dynamics
)
High Level Methylation
less active transcription
Silences genes responsible for regulating; cell growth, cell repair and cell apoptosis
=> Conducive to cancer
Chromosome stability
Low Level Methylation
more active transcription
chromosome instability (highly active DNA more likely to be deuplicated/deleted etc.)
Histone Complexes are altered through post-translation modification
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