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Cancer > Epigenetics and cancer > Flashcards

Epigenetics and cancer Flashcards

1
Q

What are epigenetic traits?

A

Stable, heritable phenotypes resulting from changes to chromatin structure without alterations to the DNA sequence

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2
Q

What alters the chromatin?

A

Chromatin remodelling proteins-

they compress or open up the chromatin

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3
Q

How do epigenetics modifications result in a different phenotype?

A

Alterations of chromatin structure results in a change in gene expression
this results in an altered phenotype

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4
Q

How are chromatin remodelling proteins regulated?

A

In a signal regulated way

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5
Q

What are the 2 main impacts of epigenetic modifications?

A
  1. They control the accessibility of target genes to incoming transcription machinery e.g RNA polymerase 2
  2. They directly control the biochemical activity of transcriptional machinery itself
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6
Q

What are the 2 main histone modifications- what do they cause?

A

Methylation and acetylation
either:
conversion of genes into active domains of transcribable chromatin
or
inactive genes of transcriptionally silent chromatin

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7
Q

What 3 things must occur for a proliferating progenitor cell to become a differentiated cell?

A
  1. Suppression of cell renewal
  2. Lineage commitment
  3. One programme of differentiation pursued
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8
Q

Where are modifications made on histones?

A

The N terminal tails of each of the 4 substituent histone components

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9
Q

What are the 4 components of a histone?

A

H2A
H2B
H3
H4

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10
Q

What is a nucleosome?

A

DNA wound around 8 histone protein cores-

building block of chromatin

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11
Q

What are the covalent modifications made to core histones?

A

Acetylation- of lysine tails
Methylation- of lysine and arginine tails
Phosphorylation- of serine 10 in histone H3

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12
Q

What is the relationship between acetylation and methylation?

A

They are competing reactions

both can occur on lysine tails

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13
Q

What are HATs and HMTs? What is their main difference?

A

HATs= histone acetyltransferases
HMTs= histone methyltransferases
HATs can modify many different lysine residues whereas HMTs are much more site specific

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14
Q

Which histone methylation modifications are associated with activation and repression?

A

Dependent on the modification and where it was made
Histone lysine 4 methylation= activity
Histone lysine 27/9= inactivity- repression

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15
Q

What is acetylation predominantly associated with?

A

Transcriptionally active chromatin

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16
Q

What is the significance of histone modifications?

A

They act as recruitment signals- they recruit parts of the transcription machinery

17
Q

What does acetylation recruit?

A

Proteins that contain an acetyl-lysine binding domain called a bromodomain

18
Q

What does methylation recruit?

A

Proteins that contain either a chromodomain (REPRESSORS) or a PHD zinc finger domain (ACTIVATION)

19
Q

What happens when genes in the ‘polycomb group gene enhancer of zeste’ are mutated?

A

Extra sex combs develop on the drosophila

normally just the forelegs

20
Q

What does enhancer of zeste code for?

A

A HMT of lysine 27- involved in converting a homeotic complex to inactive- transcriptionally repressed
when its mutated= lose the inhibition and thus develop more sex combs

21
Q

The polycomb group of proteins code for various proteins- what are the main ones?

A

Code writers- components of a complex in which EZH2 methyltransferase lies
Code readers- proteins of a complex that a chromodomain containing protein binds
The group codes for a chromatin regulatory system- which marks chromatin for silencing and makes it transcriptionally inert

22
Q

What happened when they isolated the polycomb protein genes in vertebrates? What is the relevance with prostate cancer?

A

The polycomb family of proteins are frequently and highly expressed in cancers
In normal prostate and advanced prostate cancer-
immunostaining showed that there were increased levels of EZH2 in the advanced prostate biopsies

23
Q

How can you study metastasis in cells?

A

Use a matragel membrane- punch small holes into it

invasive cells will try and squeeze through the holes

24
Q

What happens in you KO EZH2 in cells and study their ability to invade? What can be concluded?

A

Much less invasion

EZH2 is required for the metastatic phenotype

25
Q

What is EZH2 also required for?

A

Cell proliferation

26
Q

What is the mutant EZH2 protein like? Where are mutations in EZH2 common?

A

Hyper-active protein which makes it constitutively active- hyper-methylating through the genome
non-Hodgkin’s lymphoma- EZH2 is the most frequently modified chromatin modifying gene

27
Q

What else is characteristic of mutant EZH2 proteins? How is this being as a result?

A

The proteins are hypersensitive to a class of small molecule
can make specific inhibitors which target mutant EZH2 and have relatively no effect on WT EZH2
kills mutant lymphoma cells

28
Q

How does EPZ affect mutant EZH2?

A

It prevents EZH2 from methylating histone lysine 27
(in a concentration dependent manner)
Inhibits proliferation of EZH2 mutated cells- cancer specific inhibitor (conc dependent)

29
Q

What are the 2 point mutations associated with mutant EZH2?

A

Tyrosine to a phenylalanine

Alanine to a glycine

30
Q

What can aberrant crossovers due to chromosomal translocations (between non homologous chromosomes) cause?

A

The creation of hybrid genes which code for hybrid proteins- which are characteristic of many lyphomas and leukaemias

31
Q

What are the 2 cross overs associated with acute myeloid leukaemia and acute lymphoblastic leukaemia?

A

Cross over between chromosomes 8 and 16- between 2 HATs- AML
Cross over between chromosomes 11 and 16- between a HMT and HAT- ALL
Both of these translocations create fusion proteins that make a population of immortalised haemopoietic stem cells

32
Q

What are the 3 main domains of the MLL protein?

A

Catalytic domain- allows it to make methylation lysine 4 marks
Interaction domain- can bind to HATs
PHD finger domain- can bind to histone lysine 4 when its methylated

33
Q

Whats the main role of MLL?

A

To be able to recognise methylated histone lysine 4 and propagate new methylation marks on adjacent nucleosomes
=make a transcriptionally active DNA domain

34
Q

Following a leukemogenic translocation- what is lost (and retained) in the MLL protein?

A

Lost- domains involved in histone lysine 4 methylation and recognition
Retains its transcriptional repressor domain

35
Q

What can be suggested about the fusion MLL proteins new function?

A

MLL exerts its leukemogenic function by acting as a dominant negative inhibitor of its WT counterpart
It compromises the ability of target genes to be methylated- and thus activated

Cancer (16 decks)

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