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BMS 379 Cancer biology > Lecture 14 - Epigenetics > Flashcards

Lecture 14 - Epigenetics Flashcards

1
Q

What processes regulate transcription and how do they do it?

A
  • Acetylation and methylation of histones by influencing recruitment of transcription factors to target genes
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2
Q

What characteristic feature of tumours is related to epigenetic ?

A

Over expression or mutation of histone-modifying proteins

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3
Q

What are the future prospects of epigenetics ?

A

Drugs that target the epigenetic machinery are promising new anticancer agents

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4
Q

Epigenetic traits

A

are stable, heritable phenotypes resulting from changes to chromatin structure without alterations to DNA sequences

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5
Q

What is the difference between genetics and epigenetics ??

A

Genetics – Mutation of DNA > altered gene function > Altered phenotype
Epigenetic’s – alterations to chromatin structure > altered gene expression > altered phenotype

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6
Q

Through regulating chromatin structure, what do epigenetic mechanisms do ?

A
  • control accessibility of target genes to incoming transcription machinery
  • Directly control biochemical activity of transcription machinery
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7
Q

Epigenetic modifications

A

cause stable alterations to chromatin structure

and gene expression but do not change nucleotide sequence of DNA

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8
Q

Give examples of epigenetic modifications:

A
  • Histone modifications – acetylation, methylation
  • DNA methylation
  • non-coding RNAs
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9
Q

Production of differentiated cells from proliferating progenitor cells involves selective transcription of specific genes which:

A
  • suppress self-renewal
  • promote lineage commitment
  • activate one programme of cell differentiation and repress all others
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10
Q

Conrad Waddington

A

epigenetic landscape / journey all cells take through development
- intracellular signalling pathways
early development- cells lie in higher reaches not exposed to env then move through the landscape and succumb to various signals and adopt specific cell fates
sequential changes in transcriptome and proteome

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11
Q

Cancers can develop when ?

A

self-renewing stem/progenitor cells “get stuck” in the higher reaches of the epigenetic landscape

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12
Q

What causes epigenetic induced cancers ??

A

Chromatin in nucleus acquires tumour specific characteristics
Modification targeted to the N terminal tail of the histone
- covalent modifications

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13
Q

Covalent modification added to core histones

A
  • Acetylation of lysines in core histone N-terminal tails
  • Mono-, di-, tri-methylation of lysines and arginines in core histone N-terminal tails. Various residues modified by distinct enzymes
  • Phosphorylation of serine 10 in Histone H3
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14
Q

General epigenetic change that causes cancer -

A

Modify way transcription machinery interact

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15
Q

What happens to lysines if acetylated??

A

they can no longer be methylated

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16
Q

Whats the difference between HATs and HMTs ??

A

Histone Acetyltransferases (HATs) can modify many different lysine residues
in core histones whereas histone methyltransferases (HMTs) exhibit exquisite
site-specificities - “Histone Code” Writers

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17
Q

EZH2

A
  • Specific mark on histone 2 lysine 7 – implicated in cancer
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18
Q

If chromatin rich in lysine 27

A

transcriptionally inactive

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19
Q

What is the purpose of Acetylation of histones ?

A

histones creates binding sites for transcriptional

activation factors that contain a bromodomain – Histone Code Readers

20
Q

Histone code readers

A

histones creates binding sites for transcriptional

activation factors that contain a bromodomain – Histone Code Readers

21
Q

Histone code writers

A

Histone Acetyltransferases (HATs) can modify many different lysine residues
in core histones whereas histone methyltransferases (HMTs) exhibit exquisite
site-specificities - “Histone Code” Writers

22
Q

Methylation of core histones can create binding sites for

A

(a) transcriptional repressors that contain a chromodomain
(b) transcription activators that contain a PHD zinc finger domain
Recruitment of chromodomain (H3K27)
repressor
or PHD finger domain (H3K4) activator

23
Q

Epigenetic code

A

defining the parts of genome into active and inactive

24
Q

building blocks of chromatin

A

Nucleosomes

25
Q

Ed lewis

A
  • discovere bi-thorax complex in flies

- discovered genes involved in epigenetics

26
Q

Ed lewis - findings

A
  • bithorax complex and anopaedia complex two homeotic complexes in drosophila
  • Sex combs reduced gene in the anopaedia- bristle structure on foreleg in males used in matings
  • discovered mutation of sex combs reduced
  • mutaton carrys extra sex combs
  • Loss of function mutations in the Drosophila Polycomb Group gene Enhancer of zeste [E(z)] cause the development of extra sex combs on mesothoracic (second pair) and metathoracic (third pair) legs - opposite phenotype to sex combs reduced phenotype
  • evidence for widespread activity of the homeotic gene across the thorax
27
Q

Enhancer of zeste codes for what

A

Histone 3 lysine methyl transferase

  • involved in converting homeotic complex to a heavily transcription repressed locus - inactive in all parts of body apart from the first legs where there is expression of antenopaedia complex where sex combs reduced is expressed
  • animals without enhancer of zeste- chromatin cannot be repressed so ubiquitously active - thats why when mutated it is expressed in all the other legs
28
Q

Polycomb group of proteins

A

proteins that can generate or recognise repressive chromatin modifications - histone code writers and readers
- chromatin regulatory system

29
Q

Code writer

A

H3-K27methylation mediated
by the Enhancer of zeste [E(z) /Ezh2]
component of PRC2
(Code Writer)

30
Q

Code reader

A

Recruitment of PRC1 complex via
Polycomb (Pc) chromodomain-
containing component

31
Q

Polycomb proteins & cancer

A

Polycomb family proteins highly expressed in cancers
Increased expression of EZH2 protein is a characteristic feature
of advanced Prostate Cancer
biopsies – stained with antibody for EZH2
-

32
Q

PC cancer -

A

Increased expression of EZH2 is accompanied by increased H3K27methylation and decreased transcription of many genes in prostate cancer cells

33
Q

EZH2

A

promotes proliferation and invasiveness of Prostate Cancer cells

34
Q

KO – Lysine 27 methyl transferase – what happens to cells ability to proliferate ??

A

used a synthetic cell matrix and cultured cells with Luciferease SiRNA and EZH2 siRNA» shows cell proliferation significantly reduced in EZH2 siRNA

  • inhibit enhancer of zeste function
  • if cells invasive they well squeeze through the holes and migrate from one side of the matrix to the other and adhere
  • EZH2 is required for the metastatic phenotype
35
Q

Hallmarks of cancer - epigenetic

A

Increased expression of Polycomb Group proteins is a hallmark of
many different types of human cancer

36
Q

what mutation can promote tumorigenesis

- give an example

A

Mutations in genes encoding histone modifying enzymes can promote tumourigenesis
Follicular lymphoma -mutation in chromatin modifying gene mutations - lysine methyl transferase commonly mutated

37
Q

Therapy/Treatment prospects

A 
Mutated forms identified to be hypersensitive to a class of small molecules 
Selective inhibitors being discovered that target EZH2 - but little effect on WT
38
Q

Specific point mutations in EZH2 are highly associated with

A

malignant non-Hodgkin’s Lymphoma
Y641F A677G
These EZH2 mutant proteins are hyperactive and only catalyse
trimethylation of H3K27 (not able to cause mono- or di-methylation,
unlike wild-type EZH2)

39
Q

Small molecule mechanism of action

A

EPZ005687 specifically blocks mutant H3K27 trimethylation by EZH2
in a dose-dependent manner
- detected by western blotting using ABs specific H3K27 me 3

40
Q

lymphoma-specific EZH2 mutation

A

A677G catalyses exclusively
H3K27 trimethylation, which renders lymphoma cell proliferation
specifically sensitive to EPZ005687
- hypersensitive to concentrations of the small molecules
- cancer specific inhibitor of proliferation
- Wt there is no effect

41
Q

How do you create Hybrid genes/ Hybrid proteins ?

A

Chromosomal translocations due to aberrant cross-overs between
non-homologous chromosomes can disrupt genes to create hybrid genes encoding hybrid proteins

42
Q

What can cause leukaemia ?

examples :

A

Chromosomal translocations that disrupt HAT and HMT (chromatin modifying) genes can cause leukaemia
- Acute Myeloid Leukaemia - (HAT) MOZ - (HAT) CREBP fusion - Chr 8 and chr 16
-Acute Lymphoblastic leukaemia - (HMT)MLL–(HAT) CREBBP fusion
Chr11 and Chr16

43
Q

AML

A
  • Acute Myeloid Leukaemia - (HAT) MOZ - (HAT) CREBBP fusion - Chr 8p11 and chr 16p13
44
Q

ALL

A

-Acute Lymphoblastic leukaemia - (HMT)MLL–(HAT) CREBBP fusion
Chr11q22 and Chr16p13

45
Q

MLL fusion proteins

A

MLL fusion proteins drive the emergence of a leukaemic stem cell population by preventing differentiation of pluripotent haemopoietic stem cells and more committed progenitors

46
Q

MLL structure

A

Leukaemogenic translocations involving the Histone Code Writer/Reader MLL
delete its PHD finger, its Transcriptional Activation region and its H3K4
methyltransferase (SET) domain, to create a fusion protein that retains the MLL
repressor domain
- contains a catalytic domain that allows it to make histone modifications
- interaction domain that allows it to bind HATS of which CBBP is n example
-PHD finger can bind to lysine 4 when methylated can methylate proteins on lysine 4 and recognise them for methylation events

47
Q

MLL fusion protein structure

A

Loss of domains required for histone 4 methylation and recognition for methylation event
-suggestion that MLL exerts it leukaemogenic function by acting as a dominant negative inhibitor of its WT counterpart by compromising the ability of target gene to be stablished in active domain of chromatin

BMS 379 Cancer biology (18 decks)

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