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Cancer Biology T2 > L34 Epigenomics in Cancer > Flashcards

L34 Epigenomics in Cancer Flashcards

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AP® Biology flashcards Biology 101 flashcards
1
Q

What is epigenetics

A
  • in addition to the genetics - the study of changes WITHOUT ALTERATION of the genetic code itself
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2
Q

What is epigenomics

A

the study of the epigenome ALL epigenetic MODIDFICATIONS across an individuals entire genome

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3
Q

% of genome that is protein encoding

A

1% (the rest is non-coding)

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4
Q

Epi-genetics and genomics is essentially _____

A

above or in addition to the genetics/the genome

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5
Q

Epigenomics helps to understand…..

A
  • how a genotype gives rise to different phenotypes
  • how traits are inheritied
  • how structural adaptation of the genome facilitates gene activation or repression
  • most epigentic modifications are reversible
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6
Q
  • epigentic landscape
A
  • waddington
  • how genes are read during embyonic development
  • metaphor to a marble; cells take different directions
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7
Q

biological influences on the genome

A
  • either endogenous (interrnal; comes from inside cell) or exogenous (external; environmental factors):
  • cell to cell contact (very specific and precise)
  • secreted cell factors
  • homone signals (which go throughout body)
  • environmental factors (can be indirect/direct)
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8
Q

biological signifigance of the epigenome

A
  • turning genes on and off
  • structural adaptation of the genome which to register signal or maintain activity states of the DNA
  • proteins read,write, or erase these structural changes
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9
Q

covalent modification to genome

A
  • enzyme reaction takes place
  • examples:
  • post-transational histone modifications (including methylation, acetylation, phosphorylation, ubiquinations, and ADP-ribosylation
    *DNA methylation
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10
Q

histone octamer

A
  • two each of histones: H2A, H2B, H3 and H4
  • negatively charged DNA wrapped (147bp) (histones are positively charged which allows this interaction)
  • separated by linker DNA
  • histones H1 compats the string to solenoids
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11
Q

histone tail modifications

A
  • influence how closely DNA is packed
  • different amino acids do different things; for example Ardinine can be methylated; K (lysine can be both methylated or aceyltated)
  • they have different propoties
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12
Q

phosphorylation adds

A

negative charge

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13
Q

acetylation adds

A

positive charge

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14
Q

lysine…..

A

acetylation and methylation - either or but never both

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15
Q

histone modification nomenclature

A

counted from end of tail (so as you get closer to the core the number goes up) H3K9me3

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16
Q

how do histone modification impact DNA transcription

A
  • ACTIVE TRANSCRIPTION (Euchromatin)
  • weakened electrostatic interactions between DNA and histone
    *DNA is not tightly packed and permits transcription
  • REPRESSED TRANSCRIPTION (heterochromatin)
  • strong interactions between DNA andhistones
  • DNA is tightly packed, primarily inactive genes
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17
Q

ACTIVE TRANSCRIPTION

A
  • Euchromatin
  • weakened electrostatic interactions between DNA and histone
    *DNA is not tightly packed and permits transcription
  • acetylation is mainly associated
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18
Q

REPRESSED TRANSCRIPTION

A
  • Heterochromatin
    -strong interactions between DNA andhistones
  • DNA is tightly packed, primarily inactive genes
  • methylation is mainly associated
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19
Q

______ is mainly associated with Euchromatin (active)

A

acetylation

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20
Q

________ is mainly associated with heterochromatin (repressed)

A

methylation

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21
Q

histone tail methylation

A
  • in repressed - trimeth of lysine
  • whereas when of gylsine; its when in active form

If you have more than one methylation, its asoociated with active

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22
Q

proteins recognize histone modifications

A

readers, writers, and erasers

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23
Q

bromodomains and Extra-terminal domain (BET)

A
  • recognized acetylated lysine and recuit transciption factors
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24
Q

histone deacetylases (HDACs and histone acetyltransferase (HATs)

A

histone modifying enzymes

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25
Q

histone demethylases and histone methylases

A
  • specific for lysine and arginine
  • balance important in controlling the active/repressed state
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26
Q

histone modifications affect DNA- dependent processes such as:

A

transcription, splicing, replication, and repair

27
Q

histone modifications alter DNA accessibility by:

A

strengthening or weakening interactions between DNA and histones

28
Q

CpG methylation

A
  • important in transcriptions
  • important epigentic mechanism
  • happens on a CpG site (a region of DNA where we have a cytoceine followed by a theonine from the 5 to 3 prime direction
  • ## cytosine can become methylated to form a different thing (specifically in this lecture 5-methylcytosine)
29
Q

CpG methylation changes a ______ into a ______

A

cytosine into a 5-methylcytosine (the fifth base of the human genome)

30
Q

Why is there CpG deficiency in the human genome?

A
  • there are less sites than we would expect (expect 4.41% but there are actually less than 1%)
  • methylated CpG are highly mutated
31
Q

Why are CpG sites highly mutated?

A
  • spontaneaou deamination of the methylated cytosine
  • this leads to thymine
  • also to a mutation
  • leads to C to T transition
32
Q

How much % of CpG sites are methylated

A
  • 60-90%
33
Q

Where are CpG sites located?

A

> 80% total CpG content are in repetitive sequences; e.g. centromeres, telomeres, LINE, SINE elements
- 1-2% of CpG sites are in ‘CpG islands’

34
Q

CpG islands

A
  • regions in the DNA with a higher frequency of CpG sites
  • 500-3000bp long with 55% CpG content
    -associated with promoters of 70% human protein encoding genes
  • normally hypomethylated in Cancer
35
Q

What do CpG islands do?

A
  • when not methylated, enable transcription
  • when methylated, they supress gene expresion
  • often seen in cancer (when the hypermethylated islands become HYPO)
36
Q

DNA methylation

A
  • euchrmatin (active)= unmethylated cytosines
  • in heterochromatin (repressed) = methylated cytosines
37
Q

meCpG writers, readers, and erasers

A

Writers: DNMT1 DNMT3a and DNMT3b
Reader: Methyl-CpG Binding Domain (MBD) proteins
Eraser: Ten-Eleven-Translocation (TET) proteins

38
Q

DNMT1

A
  • me CpG writer
  • maintains DNA methylated of one strand
  • adds methylatioin to copied strand during transpcription
39
Q

DNMT3a and DNMT3b

A
  • me CpG writer
  • methylation of CpG sites that were previously unmethylated
  • imporantant in embryiogenesis
40
Q

Methyl-CpG Binding Domain (MBD) proteins

A
  • meCpG reader
  • recognize methylated CpG sites and typically cause gene repression by histone modification, nucleosome remodeling, and chromatin organization
41
Q

Ten-Eleven-Translocation (TET) proteins

A
  • meCpG eraser
  • role is to demethylate the methylated DNA
42
Q

Global CpG ______methylation; mainly occuring in __________ (cancer epigenetic dysregulation)

A

hypo; non-coding regions and repetitive elements
- means lower methylation than in regular cells

43
Q

Local CpG ______ methylation; mainly occurring in______ (cancer epigenetic dysregulation)

A

hyper; promoters and CpG islands
- happens early in tumorogenesis
- associated with gene silencing

44
Q

Effects of Global CpG hyp-methylation in cancer

A
  • increases genomic instability, activates ocnogenes and repetitive elements
45
Q

effects of Local CpG hyper-methylation in cancer

A
  • associated with gene silencing
  • hypermethylated tumour supressor genes (inhibits them)
46
Q

Colon Cancer Local CpG hyper-methylation Example

A

MLH1

47
Q

Breast Cancer Local CpG hyper-methylation Example

A

BRCA1

48
Q

Brain and thyroid Cancer Local CpG hyper-methylation Example

A

PTEN

49
Q

head and neck and lung Cancer Local CpG hyper-methylation Example

A

CDKN2A (p16 ink4a)

50
Q

DNA methyltransferase inhibitors DNMTi

A

prevent aberrant DNA hypermethylation of tumor supressor genes

51
Q

histone methyltransferase inhibitors

A

inhibition of EZH2 - a histone methylatransferates that associated with gene repression

52
Q

histone deacetylase inhibitors (HDACi)

A

prevents aberrant gene expression by inhibiting acetylation of histone tails leading to chromatin condensation
(so they keep the gene expression)

53
Q

bromodomain and extraterminal domain proteins hihibitors (BETi)

A

inhibition of epigenetic readers which activates gene expression

54
Q

myelodysplastic syndrome treatment is possible with __________ by using __________ which _____________

A
  • reversing CpG methylation
  • DNA methyltransferase inhibitors (DNMTi)
  • rexpressed the genes that were silenced
55
Q

myelodysplastic syndrome

A
  • group of bone cancers that mean that bone marrow does not make enough healthy blood cells
  • pathogenesis includes epigenetic dysregulation, or the hypermethylation of specific genes and promotor-associated CpG island
  • and histone modidications
  • can be treated with DNMTi
56
Q

EZH2 methyltransferase is a ______ _______ that trimethylates _________

A

histone methyltransferase; H3K27

57
Q

H3K27me3 is associated with

A

gene silencing

58
Q

EZH2 is _______ in solid tumors and _______ and lymphomas

A

overexpressed; mutated (gain of function)

59
Q

inhibitors of histone deacetylation

A
  • HDAC and BET inhibitors
60
Q

HDAC inhibitors

A
  • inhibit histone deacetylation associated with active transcription
  • considered as key epigenetic cancer therapy owing to their ability to express genes that were silenced
  • haematological malignanicy treatment (approved and in clinic)
61
Q

BET inhibitors

A
  • BET proteins recognize acetylated lysine and interact with the chromatin to change histones and transcription to infleunce gene expression
  • decrease expression of many oncogenes
  • only in trials, not yet in clinic
62
Q

somatic alteration in histones

A

oncohistones

63
Q

An oncohistone can be in _____ and they ______

A
  • both in the N-terminal tails and globular histone fold domains
  • affect function ofpolycomb repressor complex 1 and 2 (PRC1 and 2) - responsible for the trimethylation of H3K27
64
Q

PRC1 and PRC2

A
  • polycomb repressor complex 1 and 2
  • function effected by oncohistones or somatic alterations in histones

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