Control of gene expression 2 Flashcards
What is the definition of epigenetics?
“heritable changes in gene activity/expression which occur without changes in the DNA sequence”
Epigenetics and disease?
- Epigenetics provides the missing link on how the environment can change the cell without causing mutation to cause disease
Studies have shown that modifications can be passed down from generation to generation and can be associated with causing or predisposing disease in offspring.
What are two ways of modifying the expression of DNA without modifying the sequence?
- Histone modification
- DNA methylation
How is human DNA stored in chromosomes?
Human DNA: 2 metres long Human nucleus 10 μm wide
The DNA needs to be compacted by a factor of 10,000.
How is DNA packaged at different levels?
DNA is compacted via interaction with histone proteins
A mixture of DNA and histone protein is referred to as “chromatin”.
Chromatin is the template for epigenetic phenomena
What is a nucleosome?
Histones + DNA
A nucleosome is a basic unit of DNA packaging in eukaryotes, consisting of a segment of DNA wound in sequence around eight histone protein cores.
The histone proteins act like a spool that DNA can be wrapped around.
146bp of DNA are wrapped 1.7 times around an octomer of core proteins to form a nucleosome
Arrays of nucleosomes form the basic unit of chromatin
What are histone tails?
How can they be modified?
Basic proteins that contain a globular head domain and a charged N-terminal tail.
Modifications:
The tails extend outwards, are largely unstructured and targets for modifications such as acetylation, methylation, phosphorylation.
The modifications alter chromatin structure by changing condensation and thereby affect DNA-protein binding
Modifications of the tails are involved in global gene regulation
Explain how DNA methylation works
- Cytosine can be methylated at position 5 by an enzyme DNA methyltransferase
- Methylation takes places after DNA replication
- One of the few natually occurring modifications of DNA
- Cytosines which are 5 prime of guanines (i.e CG also called CpG) are the only base which is methylated.
- Methylation of cytosine can affect gene expression by switching it off.
Explain how cytosine methylation works
The methylation at the 5 position does not interfere with base pairing of cytosine with guanine.
The methyl group protrudes from the major groove where is creates a novel epitope which has the potential to interact with proteins.
Methylated DNA can be more compactly packed than un-methylated DNA, so it can be like an ‘off’ switch.
What is the evidence for methylation?
Restriction enzymes (recognising the same sequence).
What are CpG islands?
CpG dinucleotides are non randomly distributed in the human genome. There are many places where they are under represented, these tend to be coding regions of genes, repetitive regions, telomeres, e.c.t
However there are other regions in the genome which are called CpG islands because they are so rich in CGs. They can have as much as 60% C+G. This tend to be u[stream of genes/coding regions
50-60% of CGs are methylated
When does methylation take place?
Methylation patterns are copies from parental to daughter strands after DNA replication (methylation after DNA replication)
De novo methylation can take place in stem cells or cancer cells.
Problems in DNA methylation may be the cause of many diseases.
When does cytosine methylation occur in mammals?
- Gene expression
- Chromosomal stability
- Cell differentiation
- Imprinting
- X-inactivation
- Carcinogenesis
- Aging
Genes on or off or both?
Histone modifications:
Methylation
Acetylation
Phosphorylation
DNA methylation
Both
Both
On
Off
