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BMS379 Cancer Biology > Lecture 10 Epigenetics and Cancer > Flashcards

Lecture 10 Epigenetics and Cancer Flashcards

1
Q

What are the two ways that regulating chromatin structure can be used to regulate gene expression

A

Controlling the accessibility to target genes of the transcription machinery and controlling the biochemical activity of the transcriptional machinery itself

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2
Q

How do epigenetic modifications differ from genetic modifications

A

Epigenetic modifications cause stable alterations to the chromatin structure but unlike genetic alterations these are reversible and do not involve changing the nucleotide sequence of DNA

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3
Q

What are the three broad categories of epigenetic modifications

A

Histone modifications (acetylation and methylation) DNA methylation and non-coding RNAs

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4
Q

What was Conrad Waddington’s contribution to the field of epigenetics

A

Conrad Waddington suggested that different cell fates during development are the end results of distinct journeys through an epigenetic landscape

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5
Q

In order for a haematopoietic stem cell to produce differentiated leukocytes and erythrocytes what phenomena need to occur

A

It needs to repress its ability to self-renew activate of program of lineage commitment and execute a program of terminal differentiation

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6
Q

What structures are referred to as the building blocks of chromatin

A

Nucleosomes

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7
Q

What is the effect of covalent modification of nucleosomes

A

Nucleosomes can be covalently modified which act as structural changes to the chromatin that effect gene transcription

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8
Q

What is significant about the tails of core histones

A

Nucleosome core histones have N-terminal lysine rich tails which project radially from the core. These can be reversibly covalently modified

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9
Q

Which residues are commonly acetylated by histone acetyltransferases

A

Lysine residues

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10
Q

Histone methyltransferases mono di or trimethylate which amino acids within the histone tails

A

Lysine and arginine

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11
Q

Acetylation and methylation of core histone tails can occur simultaneously T or F

A

F – methylation and acetylation are mutually exclusive and are competing modifications

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12
Q

Production of methylation marks prevents acetylation T or F

A

T

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13
Q

Histone acetyltransferases can modify many different lysine residues T or F

A

T

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14
Q

Histone methyltransferases can modify many different lysine or arginine residues T or F

A

F – histone methyltransferase exhibit exquisite site specificities

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15
Q

How many different enzymes methylate lysine 4 residues

A

6 different enzymes

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16
Q

How many different enzymes methylate lysine 9 residues

A

5 different enzymes

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17
Q

Which residues are methylated by CARM1

A

Arginine 17

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18
Q

Enhancer of zeste is one enzyme that methylates a lysine residue. What position in the polypeptide chain does it act

A

EZH2 methylates lysine 27

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19
Q

What is the role of EZH2 in development

A

EZH2 is a gene required to repress Hox gene expression in a specific anterior-posterior fashion

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20
Q

Histone methyltransferases act as regulators of gene transcription and are uniquely site specific T or F

A

T

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21
Q

Histone acetylases are uniquely site specific T or F

A

F – they acetylate a number of different lysine residues

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22
Q

What is meant by histone code writers

A

Histone methyltransferases are histone code writers they act as an additional code on top of the genetic code i.e. epigenetic to

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23
Q

What are the names of the enzymes that reverse histone acetylation and methylation respectively

A

Histone deacetylase and histone demethylase

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24
Q

Reversibility of the acetylation and methylation of histones accounts for what attribute of epigenetic changes

A

Means that they can be removed – aren’t permanent

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25
Q

Lysine acetylation is an indication of what

A

Transcriptionally active genes

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26
Q

Methylation can denote transcriptionally active or inactive genes depending on the loci of the residue. Determine whether methylation of lysine 4 9 27 and arginine 17 denote transcriptional activation or repression

A

Arginine 17 and Lysine 4 – transcriptionally active. Lysine 9 and 27 – transcriptionally inactive

27
Q

How does methylation and acetylation of histone influence transcription

A

Acetylation and methylation marks in general create binding sites for transcription factors

28
Q

Specifically what is the effect of histone acetylation on gene transcription

A

Acetylation of histones creates binding sites for transcriptional activation factors that contain a bromodomain. Histone Acetylation is associated primarily with transcriptionally active promoter sequences.

29
Q

Will genes that are more transcriptionally active show higher or lower levels of acetylation

A

Higher

30
Q

Methylation of core histones creates binding sites for transcriptional repressors that contain what kind of domain

A

Bromodomain

31
Q

Methylation of core histones creates binding sites for transcriptional activators that contain what kind of domain

A

PHD finger domains

32
Q

Which type of transcription factors will bind to methylated lysine 4 and arginine 17 residues

A

Transcriptional activators containing PHD fingers

33
Q

Which type of transcription factors will bind to methylated lysine 9 and 27 residues

A

Transcriptional repressors containing bromodomains

34
Q

What is the role of the polycomb family of genes in development of the Drosophila

A

Polycomb genes are developmental regulator of hox gene expression

35
Q

What is the result of mutation in polycomb proteins in Drosophila embryos

A

Mutations in polycomb genes cause a global derepression of hox gene expression in the Drosophila embryo resulting in a loss of patterning

36
Q

Enhancer of zeste is a histone modifying enzyme in Drosophila that is involved in hox gene expression. What specific histone enzyme is it and where does it act

A

Enhancer of zeste is a histone methyltransferase responsible for the methylation of histone H3 on lysine 27 residues

37
Q

What are the two mammalian homologues of enhancer of zeste

A

EZH1 and EZH2

38
Q

What is the complex formed by EZH2 in mammals that is responsible for regulating hox gene expression

A

Polycomb repressive complex 2

39
Q

PRC2 complexes include proteins that generate and recognise repressive chromatin modifications T or F

A

T

40
Q

What is the catalytic subunit of PRC2

A

EZH2

41
Q

What is meant by a code reader

A

A code reader is a transcription factor recruited by modified histones. They often contain bromo or chromodomains

42
Q

How do the PRC1 and PRC2 complexes in mammals differ

A

PRC1 complexes are histone code readers whilst PRC2 complexes are histone code writers

43
Q

What is the significance of EZH2 in prostate cancer

A

Overexpression of EZH2 protein is a characteristic feature of advanced prostate cancer

44
Q

What is the result of siRNA knockdown of EZH2 in a prostate cancer cell line

A

Knockdown of EZH2 causes a decrease in proliferation of cells as well as a decreased invasiveness

45
Q

Other than prostate which cancers often see a EZH2 overexpression

A

Bladder breast Hodgkin’s lymphoma and liver

46
Q

Mutations in genes encoding histone modifying enzymes can promote tumorigenesis. What is often the effect of these mutations

A

They often create hyperactive forms of the enzyme

47
Q

How are point mutations in histone modifying enzymes associated with cancers

A

Point mutations affecting the catalytic activity of histone methyltransferases are associated with lymphomagenesis

48
Q

Other than point mutations what mutations affecting the catalytic activity of histone methyltransferases/acetyltransferases (code writer functions) or code reader function are associated with leukaemogenesis

A

Translocations

49
Q

Give an example of a lymphoma associated with a mutation in a histone methyltransferase

A

Diffuse large B cell lymphoma (DLBCL) is characterised by mutations in the histone methyltransferase MLL2

50
Q

Which two mutations in EZH2 have been found in lymphoma cells

A

Y641F and A667G

51
Q

What is the effect of the mutations in EZH2 on the function of the methyltransferase

A

The Y641F and A677G point mutations increase the catalytic activity of EZH2. Specifically they increase the trimethylation of H3K27 rendering the enzyme no longer able to mono or dimethylate lysine 27. This causes the cells to have a selective growth advantage with decreased apoptosis

52
Q

EPZ005687 was the first example of a small molecule inhibitor of EZH2. Describe how it acts

A

EPZ005687 blocks the ability of mutant EZH2 to trimethylate H3K27 without impeding the activity of wild type EZH2 to mono or dimethylate H3K27. This results in an inhibition of proliferating lymphoma cells by inducing their apoptosis

53
Q

Below is some data on the effect of EPZ005687 on lysine trimethylation in cells with the mutant EZH2. Describe what this data shows

A

There is a dose dependent decrease in specifically lysine 27 trimethylation

54
Q

What phenomena is seen in the lymphoma cells that are expressing mutant EZH2. How is the beneficial in potential treatments of cancer

A

These cells are constitutively dependent on the mutant form of EZH2 a phenomenon known as addiction to an oncogene. This however means that Inhibition of the activity of this oncogene is specifically lethal to the mutant cells

55
Q

Give an example of a chromosomal translocation that disrupts HAT and HMT genes and can cause leukaemia

A

Acute myeloid leukaemia (AML) can be caused by the fusion of the HAT MOT from chromosome 8p11 to the CREBBP HAT gene from chromosome 16p13

56
Q

What chromosome translocation has been implicated in acute lymphoblastic leukaemia

A

A fusion of the histone methyltransferase MLL from chromosome 11q22 to the CREBBP HAT gene from 16p13

57
Q

How do MLL fusion proteins drive the emergence of leukaemic like cells

A

They can induce a leukaemic stem cell population by prevent the differentiation of pluripotent HSCs and more committed progenitors resulting in a permanent self-renewal

58
Q

What kind of histone modifying enzyme is MLL

A

MLL is a histone 3 lysine 4 methyltransferase involved in transcriptional activation

59
Q

MLL possesses a transcriptional repression domain T or F

A

F – it possesses a transcriptional activation domain

60
Q

What is the significance of MLL possessing a PHD finger domain

A

These domains are usually present in the transcriptional activators recruited to lysine methylations. THs implies that MLL is both a histone code reader (due to its methyltransferase domain) and a code reader.

61
Q

What is significant about the domains of MLL during chromosomal translocations

A

Almost all translocations involving MLL remove the PHD transcriptional activation and SET domains. This hence results in an overall removal of the activation elements of the protein

62
Q

How can translocations of the MLL gene account for its role in cancer

A

Removal of the activation elements of the MLL protein will result in a loss of transcriptional activation. This can be linked to a failure of the cell to commit to a differentiation programme which would require gene transcription. This may provide the mechanism by which these progenitor cells get stuck in a state leading to continued self-renewal

63
Q

What is meant by the achilles heel of MLL cancers

A

Because these cancers have lost functional MLL they are more susceptible to the inhibition of other histone methyltransferases

64
Q

EPZ-5676 is an inhibitor of another histone methyltransferase DOT1L. How has this been used as a therapeutic target in leukaemia

A

Cells will have become much more critically reliant on the DOT1L methyltransferase when there is a loss of function of MLL. Hence EPZ-5676 has been found to be effective in the treatment of leukaemia’s involving an MLL fusion where by it has been able to these leukemic cells

BMS379 Cancer Biology (10 decks)

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