Epigenetic Mechanisms

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A CpG site is a region of DNA where a cytosine lies next to a guanine.

A CpG island is a region of DNA that has multiple CpG sites.

DNA methylation occurs at CpG sites, where methyl groups are added to the 5' position of cytosine to form 5-methyl cytosine (5MeC)

NB This doesn't affect how bases pair because the methyl groups are on the outside of the double helix

This methylation allows various proteins to bind which lead histones to become deacetylated causing them to organise into tightly packed nucleosomes

This means that transcription activator complexes can not access the area

In general, methylation suppresses gene expression

Modification of Histones:

Histones are subject to a wide range of modifications of their amino acid tails:

o Methylation and acetylation of lysine residues

o Phosphorylation

o Attachment of ubiquitin

HOW DO THESE MODIFICATIONS CAUSE A CHANGE IN TRANSCRIPTION RATE?

Cis model

Acetylation of the amino acid chain can neutralise the positively charged amine group. This means that the negatively charged DNA is bound more loosely to the histone and so is more accessible for transcription

Trans model

The hypothesis that these modifications alter gene transcription is called the ‘histone code’

o The histone modifications serve to recruit other proteins which specifically recognise the alteration

o These proteins then alter chromatin structure to modify transcription

When DNA is replicated it is not methylated so maintenance methylase enzyme methylates

any CpG on the new strand according to what is methylated on the paternal

strand

This means that Epigenetics can produce heritable changes without changing the DNA sequence.

MECP2 (mutation in Rett Syndrome)

MBD1 these are proteins that bind to methylated DNA, suppressing transcription

HDAC = histone deacetylase

Steps:

At the start: DNA is methylated

1) Proteins MECP2 and MBD1 bind to the methylated DNA

2) These proteins recruit histone deacetylases and histone methyltransferases

3) Histones become deacetylated (see Modification of Histones) and methylated

4) Methylated histones bind chromodomain proteins

5) Chromodomain proteins recuit methytransferases

6) These methylate DNA

DNA methylation

Modification of Histones

Interdependence of two processes

Replication