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cancer > 12. cancer epigentics 1 > Flashcards

12. cancer epigentics 1 Flashcards

1
Q

define two things that cause cancer

A
  1. DNA mutations - can affect protein coding, regulatory region, introns and splicing
  2. mis-regulation of gene expression - DNA mutation independent/epigenetics
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2
Q

what is epigenetics

A

heritable changes in gene expression that do not involve changes to the underlying DNA sequence
i.e. changes in phenotype without changes in genotype

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3
Q

what is Lamarckian inheritance

A

the theory an organism can pass on characteristic that it has acquired in its life
>generally dismissed
>recent epigenetics have shown some truth in this - well documented in plants and worms by small RNA that can last 20 generations in worms

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4
Q

what are two pieces of evidence that our interaction with the environment can affect our offspring

A
  • the Dutch famine

- Canadian ice storm

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5
Q

what was seen in the Dutch famine?

A

people born in dutch famine have hypomethylation on IFG2 gene when analyses 6 decades later
>protein deficient diet from mother contributed to the loss of DNA methylation in IGF2 gene
>the mothers environment affected the methylation state of the children’s’ DNA

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6
Q

what was seen in the Canadian ice storm?

A

children born while mothers were in this period had widespread changes in the epigenetic state and this correlated to how stressed the mothers were - led to behavioural and learning difficulties

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7
Q

name four types of epigenetics

A
  • DNA methylation - repressed expression
  • histone modification - activate and represses gene expression
  • chromatin remodelling - activate and represses gene expression
  • non-coding RNAs - in general repress gene expression
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8
Q

what is DNA methylation and where does this occur?

A

covalent attachment of methyl group onto cytosine in DNA

>this happens at CpG sites

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9
Q

the CpG site is fully methylated if both the cytosine’s are methylated. what happens when the cell divides?

A

there is only one methylated cysteine

DNMT1 methylates the other cysteine so they cell can maintain its methylation state.

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10
Q

in addition to repression of gene expression what does methylation of CpG islands also supresses?

A

> nearby transposable elements

>also involved in X inactivation

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11
Q

what happens with a father has a methylated gene and the mother does not?

A

the mothers gene will be expressed in the offspring

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12
Q

how can DNA methylation be implicated in cancer?

A
  • if you hyper-methylate a tumour suppresser then it will be turned off
  • if you remove the methylation from an oncogene then it will be turned on
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13
Q

what are the two mechanisms that DNA methylation uses to repress gene expression?

A
  • recruitment of complexes to repress transcription

- blocking TF binding

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14
Q

describe how DNA methylation lead to recruitment of complexes to represses transcription (the major mechanism of repression)

A

repression complexes recruited through methyl CpG binding protein
e.g. HDAC recruited by these proteins - represses chromatin

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15
Q

describe how DNA methylation can block TF binding and comment on this

A

either TF can bind methylated DNA or
methyl CpG binding protein blocking them from binding
>this is restricted to a few special cases

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16
Q

hypomethylation in cancer can lead to aberrant expression of what three types of genes?

A
  • transposable elements – can integrate at random sites and cause genomic instability
  • viruses which may have been dormant e.g. activation of oncogenes
  • individual genes
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17
Q

hypermethyaltion of what genes can result in tumourigenesis?

A
  • TS - e.g. the cell cycle inhibitor p16
  • DNA repair - lead to genomic instability e.g. BRAC1 (homologous recombination)
  • cell adhesion - repression of E cadherin can promote metastasis
  • cell death genes
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18
Q

what gene is hypermethyalted in liver cancer?

A

p53 - represses expression

there are no classical CpG islands upstream of this but it is still pressed by C methylation

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19
Q

how do you tell if CpG is methylated?

A

bi-sulphate treatment
>converts the non-methylated cytosine’s to uracil and the methylated cytosine’s are protected
>sequence sample (sanger/high-throughput)
>all cytosine’s in sequence were methylated

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20
Q

what can prevent oncogene activity?

A

DNA methylation -prevent transcription factors from binding e.g. methylation of E box site prevents Myc binding

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21
Q

describe chromatin

A

histones package and order DNA intro structural units called nucleosomes
>Each nucleosomes consists of eight histone proteins (DNA wraps 1.65 times around)

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22
Q

name 5 types of histone PTM and what do they do?

A
  • lysine acetylation
  • lysine and arginine methylation
  • serine and threonine P
  • lysine ubiquitination
  • lysine sumolation
    >affect how histones interact with DNA and other histones
23
Q

how can histone modifications affect each other?

A

there is histone modification cross-talk where modifications feed-back and promote/inhibit the modification at another site

24
Q

how do histone modification impact on the chromatin state?

A
  • altering the electrostatic charge pf the histone, resulting in structural changes in histone binding to DNA
  • modifications are binding site for protein recognition modules, which recruit chromatin remodellers
    >these affect how genes are expressed
25
Q

define the three activating histone modifications

A

H3K9 acetylation
H3K27 acetylation
H3K4 methylation

26
Q

define the 2 repressive histone modifications

A

H3K9 methylation

H3K27 methylation

27
Q

what are the readers in the histone code?

A
  • chromodomains bind to methylated lysine

* bromodomains bind acetylated lysine

28
Q

what are the writes in the histone code?

A
  • histone acetylators (HATs)
  • histone deacetlators (HDACs)
  • histone methylases
  • histone demethylases
29
Q

what are currently in clinical trials? and is a problem with this?

A

HDAC inhibitors

>they target enzyme globally and so could affect gene expression of non-target genes

30
Q

when mutations arise in DBD of p53 what may occurs?

A

no longer bind places it should bind and can bind genes which its wild type form does not - they can bind chromatin remodellers (e.g. MLL1) and these drive activating histone modifications
>thought to promote expression of oncogenes

31
Q

what was shown about chromatin remodeller MLL1 that drive active histone modifications and its affect on tumour growth?

A

MLL1 upregulation impacts tumour growth

- when KO MLL in these gain of function p53 there is slowed tumour growth in comparison to non KO

32
Q

what was discovered in Drosophila 60 years again? and what does it do?

A

they polycomb complex
>general repressor of hoemtic genes (specify different segments of body in development - these are expressed in same order they are found on chromosome)

33
Q

what is the polycomb complex made up of? and what type of proteins are these?

A

2 complexes
PRC1
PRC2
>both reads and writes parts of the histone code

34
Q

what are is the polycomb complex known to be involved in?

A

development, stem cell plasticity and cell cycle control

35
Q

how does the polycomb complex function?

A

> PRC2 binds DNA and methylates H3K27
CBX recognises H3K27me and recruits PRC1
PCR1 ubiquitinates H2AK119

36
Q

how might PRC2 be recruited to the DNA?

A

TFs / RNA

37
Q

what is the enzymatic unit of PRC2?

A

EZH2 - histone methyltransferase

38
Q

what are the four ways that polycomb complexes represses transcription?

A
  • chromatin compaction
  • recruitment of DNMTs
  • blocking RNAP
39
Q

what histone code cross talk is seen by the polycomb complex?

A

H3K27 methylation promotes H2AK119 ubiquitination

40
Q

the polycomb complex promotes self-renewal of stem cells - how does it help tumourigenesis?

A

by blocking differentiation and so keeping cells dividing

41
Q

what does enhanced levels of EZH2 do in some cancer? give another example where polycomb is implicated in cancer

A

promotes the growth

>part of PCR1 (Bmi1) plays key role in lung tumourigenesis

42
Q

why is polycomb implicated in cancer?

A

repressing tumour suppressers and promoting tumour progression

43
Q

what is found in >90% colorectal cancers? how can this tumour be rescued?

A

> silencing of HAND1
enriched EZH2 and H3K27me at HAND1 gene
HAND1 re-expression prevents proliferation and further tumour formation

44
Q

what is heterochromatin?

A

highly dense chromatin

45
Q

name a key component of heterochromatin and what does it recognises?

A

HP1 (heterochromatin protein 1)

>H3K9 methylation through chromodomains

46
Q

what does HP1 do?

A

facilitate the spreading of heterochromatin through the recruitment of H3K9 methylase

47
Q

the establishment of heterochromatin is not yet fully clear, what is known?

A
  • HP1 recruited by TFs
  • H3K9 methylases by RNAi machinery
  • more HP1 can be recruited with the increase in H3K9 methylation
48
Q

which histone interacts with HP1 and H3K9 methylase and why?

A

histone H1
>to facilitate chromatin compaction - binding of linker histone helps form secondary structure of chromatin - solenoids formed to reinforce compressed state

49
Q

how is HP1 implicated in cancer?

A

reduction in HP1 is associated with cancer progression - this is likely to do with the role of HP1 is centromere stability, telomere capping and regulations of euchromatic and heterochromatic gene expression

50
Q

although reduction in HP1 is seen to cancer progression, what three types of cancer has H3K9 repressive histone modification overexpression?

A

breast - H3K9 methylases overexpression activates cells migration
colon cancer - H3K9 increased in invasive regions
leukaemia - H3K9 methylases promotes leukaemia progression and when inhibited prevents cancer

51
Q

what determines whether something like the polycomb complex will lead to cancer?

A

the cellular content

52
Q

describe how over expression of polycomb complex may or may not lead to cancer

A

> polycomb binds TF and prevents expression of TS
polycomb may be over expressed in both cells types
but if one types doesn’t express TF polycomb will not bind

53
Q

give another example of how over expression of polycomb complex may or may not lead to cancer

A

> different cell types have different threshold of tumour suppresser levels
polycomb repression in one cell type might bring TS below threshold value and might not in another
higher threshold may lead to cancer

54
Q

what implications does cellular context have on therapy? (3)

A
  • tailoring therapy based on cell type of origin
  • tailoring therapy on individuals genome and epigenetic state of the tumour
  • personalised medicine

cancer (24 decks)

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