Epigenetics 1 Flashcards
When did the Dutch famine occur?
1944-1945
What was the epigenetic consequence of the Dutch famine?
The IGF2 promoter of children conceived in this period was hyper-methylated. This resulted in slower metabolic rate, leading to obesity and cardiovascular disease.
When was the Canadian Ice Storm and what was its epigenetic consequences?
1998 - higher stress levels in pregnant woman resulted in epigenetic changes in children associated with learning/behavioural difficulties.
Where does nearly all DNA methylation occur?
On cytosine bases of CpG islands.
What can methylation of CpG islands cause?
Silencing of nearby genes, genetic imprinting, X inactivation and transposable element silencing.
In cancer, which genes tend to be hypomethylated and which genes tend to be hypermethylated?
Hypomethylated - oncogenes, TEs, viral genes (aberrant expression)
Hypermethylated - tumour suppressors (silencing)
What can be recruited by methylation of CpG islands?
Proteins with MBD - for example HDAC, which tightens DNA.
What can MBD binding result in?
Prevention of TF binding.
Why is p53 not often mutated in liver carcinomas?
Because the promoter is hypermethylated.
How can methylated cytosines be identified?
Treat DNA with Bisulphite, which converts non-methylated cytosines to uracil. Any cytosines remaining will be those that are methylated.
Describe the structure of a nucleosome.
(H2A, H2B, H3, H4) x 2 = 8 subunits
How many base pairs of DNA are wrapped around a nucleosome?
~170bp of DNA
What PTMs can be added to histones?
Lysine acetylation/ubiquitination/sumoylation
Lysine/arginine methylation
Serine/threonine phosphorylation
What is ‘histone modification cross talk’?
This is when one PTM on a histone promotes/represses the modification of another histone site.
What are the activating modifications of H3?
Acetylation of H3K9 and H3K27.
Methylation of H3K4.
What are the repressive modifications of H3?
Methylation of H3K9 and H3K27.
What are bromo and chromo domains? and what complex contains two chromo domains?
Bromodomains bind lysine acetylation.
Chromodomains bind lysine methylation.
Complex = NuRD complex
Where do gain of function mutations in p53 tend to be?
In the DBD
What do gain of function mutations in p53 often cause?
Change in specificity of binding or increased affinity for same genes.
What are examples of new binding partners of a p53 gain of function mutant?
MLL1 - methyltransferase which leads to methylation of H3K4.
MOZ - HAT, leads to H3K9 acetylation
Which genes does the Polycomb complex normally repress?
Homeotic genes during development
Is the Polycomb complex in cell cycle control, stem cell plasticity and cell fate?
Yes
Describe briefly the mechanism of the Polycomb complex.
- PRC2 binds to the DNA via TF or RNAP and methylated H3K27 via EZH2.
- This recruits CBX, which in turn recruits PRC1.
- PRC1 is ubiquitinates H2AK119 preventing RNAP binding.
What is the Polycomb repression mechanism an example of?
Histone modification cross talk.
How is the Polycomb complex involved in cancer?
Blocks differentiation and promotes stem cell renewal when mutated.
What is bmi-1?
Part of PRC1 - inhibits p16/ARF genes
What TF is repressed by the Polycomb complex in colorectal cancer?
HAND1
What does HP1 stand for?
Heterochromatin protein 1
What is the function of HP1?
Can recognise methylated H3K9 via chromodomain and facilitate the spreading of heterochromatin (tight packing) by recruiting H3K9 methylase
What else can HP1 interact with? and what does this cause?
SUV39H - causes solenoid formation.
Is a reduction or an increase of HP1 associated with cancer?
Reduction of HP1
