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BMS242 Cell and Molecular > L10 - Chromatin Modifications > Flashcards

L10 - Chromatin Modifications Flashcards

1
Q

Characteristics of epigentic inheritance

A

Change to the chromatin structure
Stable changes to gene expression
Erased in the germ line
Reversible

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2
Q

Characteristics of genetic inheritance

A

Change to the DNA base sequence
Can be repaired if recognised (e.g. nucelotide excision repair) if not recognised then they are permanent
If in a somatic cell (passed into all progeny)
If in a germ cell passed into all of the cells of the offspring

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3
Q

Describe the metaphor for the epigentic landscape

A

Like a ball (early ES cell) rolling down a hill

Series of valleys (fates_ and obstacle which the cell must overcome to reach its sepcialised cell fate

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4
Q

How many BP of DNA wrap around a histone

A

144 bp

Wrapped twice

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5
Q

How many subunits of the histone

A

8

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6
Q

What are the N terminal tails of the histone octomer

How do these project

A

2 of each: H2A H2B H3 H4

Project into free space which allows them to be modified

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7
Q

Describe the characteristics of closed chromatin

A

Concdensed
Topology makes it hard for RNA pol 2 to bind
Histones are closely associated to the DNA

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8
Q

Describe the characteristics of open chromatin

A

Sometimes dissociated from the DNA

RNA pol II able to bind

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9
Q

What are the 3 modifications which can be made to the chromatin

A

Acetylation of lysines
Mono, di, tri methylation of lysines and arginines
Phosphorylation of serines

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10
Q

Acetylation and methylation can both occur to which AA

Can these both occur at the same time

A

Lysine

No these are chemical modifications

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11
Q

Describe the side chain of lysine

A

4(CH2) - NH3

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12
Q

Describe how acetylation of lysine occurs

What is the name of this new structure

A

Final N -H(C(CH3)O)

Aceyl lysine

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13
Q

What enzymes add acetyl groups to lysines

What is the specificity of these enzymes

A

Histone acetyltransferases

Can add acetyl groups to many different lysines

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14
Q

What enzyme methylated lysines

What is the specificity of these enzymes

A

Histone methyltransferases

Exhibit equisite site specificity

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15
Q

What lysines/argines can be methylated of histone tail H3

A

H3K4 H3K9 H3K27 H3R17

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16
Q

What are some types of histone acetyltranferases

A

CREB binding protein

PCAF GCNS

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17
Q

What are the two code erasers (for methylation and acetylation)

A

Histone deacetylases

Histone demethylases

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18
Q

What are the two code wirters (for methylation and acetylation)

A

Histone acetyltransferase

Histone methyltransferase

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19
Q

Does acetylation cause activation or inactivation

A

All acetylations are activators

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20
Q

Does methylation cause activation or inactivation

A

Depends which residue is methylated

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21
Q

Two residues that can be methylated to activate the chromatin

A

H3K4 H3R17

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22
Q

Two residues that can be methylated to INactivate the chromatin

A

H3K9 H3K27

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23
Q

How does acetylation cause transcriptional activation

A

Creates a binding site for proteins with a bromodomain

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24
Q

Describe the bromodomain transcription activator

A

An epigenetic code reader

Affinity for bidning is higher when there are many resides which have been modified

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25
Q

What does methylation of core histone N terminal tails create binding sites for

A

Transcription repressors which contain chromodomaisn
Transcriptional activators which contain a PHD zinc finger domain

DEPENDS ON WHICH RESIDUE IS METHLYATED

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26
Q

How do transscription activator proteins act in combination with a chromatin remodelling complex

A

Selective nucelosome remodelling
Selective histone remodelling
Selective histone replacement

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27
Q

How do transscription activator proteins act in combination with a histone modifying enzyme

A

Selective histone modifcations causing the recruitment of code writers and code readers

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28
Q

What are the ways in which transcriptional repressors work in chromatin

A

Competitive binding with the activator for the DNA
Masking of the activation surface
Direct interaction with general transcription factors

Recruitment of chromatin remodelling complexes
Recruitment of histone deacetylases
Recruitment of histone methyltransferases

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29
Q

What is the polycomb group of proteins

A

Polycomb repressive complexes (PRC)

Includes proteins which are able to generate/read repressive chromatin modificaitons

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30
Q

What type of the system in the polycomb (PRC)

A

Histone code reading and code writter

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31
Q

Are chromodomains associated with transcription activation or inactivation

A

Inactivation

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32
Q

PRC2

A

Makes the mark triggering transcriptional repression

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33
Q

PRC1

A

Maintains the repressed state (chromodomain)

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34
Q

What does PRC2 require inorder to be able to function

What is the action of this component

A 
Requires EZH2 (enhancer of zeste)
This is what actually methyaltes (e.g. H3K27)
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35
Q

Once PRCR and EZH2 has performed the methylation of the H3K27 what occurs

A

Recruitment of PCR1 with polycomb chromodoation (code reader) formation of silent/repressed chromatin

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36
Q

How can cytosine be modified

What enzyme is responsible for this

A 
Can be methylated 
DNA methyltransferases (DNMTs)
37
Q

What is the interaction between DNMT and histone methyltransferase EZH2 `

A

Physical interaction

Mutually reinforce each others effects

38
Q

What are transcriptionally inactive promoters rich in

A

Methylated CpG dinucleotides

39
Q

What binds to methylated CpG dinucleotides

A

Methyl CpG binding protein 2 (MECP2)
Interact with the histone deacetylases and and histone methyltransferases in order to transform acetylated nucleosomes to methylated nucleosomes

40
Q

Why is X inactivation required

A

In males XY, there is only one dose of X linked genes, important that this is conserved in female cells

41
Q

What determines which X chr is silenced

A

One in each cell is silenced in each somatic cell in the early embryo - ONCE DONE THIS IS PERMANENT
RANDOM

42
Q

The silencing decision is then

A

Propagated clonally

43
Q

Calico cats are exlusively

A

Female

44
Q

Descirbe how the calico cat shows evidence of X inactivation

A

Fur colour on X chromsome
Heterozygous for fur colour - random which X chr get silenced in the embryo so random pigmentation (orange/black) of the fur

45
Q

Describe the mechanism by which one X chromsome is silenced

A

Synthesis of non-coding RNA - (xist RNA) from the X inactivation centre (XIC) of the Chr destined for inactivation
Xist RNA binds to the X chr in cis and promotes chromatin condensation which spreads from the XIC in both directions
Xist RNA also recruits histone modififying enzymes and other poly comb components leading to H3K27 AND H3K9 methylation of core histone N-temrinal tails also promotes deacetylation

46
Q

What forms as a result of X inactivation

A

A barr body - region of highly condensed X chromosome at the periphery of the nucleus of female somatic cells

47
Q

What maintains the expression of the active X

A

Unknown ammount of an unknown autosomal activator

48
Q

What can also effect DNA methylation

A

Dietary components (e.g. a diet high in methyl donors)`

49
Q

Describe the Agouti gene

A

Codes for yellow fur and obesity - constitutively high expression of the agouti protein

50
Q

What element does the agouti gene contain

A

IAP element which strongly activates the gene but is also highly sensitve to DNA methylation

51
Q

How can the w/t mouse phenotype be restored

A

Diet high in methyl donors causes methylation of that gene and a rescue of the phenotpye

52
Q

What is the key difference between genetic and epigenetic modifications

A

Genetic alterations occur to the DNA sequence directly and permanently affect gene expression. Epigenetic alterations occur to chromatin structure and act to modulate gene expression. These do not alter the DNA sequence and are reversible

53
Q

Epigenetic modifications facilitate stable changes in gene expression which may persist or the life of the cell of organism but are erased in the germ line, T or F

A

F – whilst the statement is true, epigenetic modifications are transferred to the progeny these cells can then decide whether to remove the epigenetic change

54
Q

How did Conrad Waddington describe how cells differentiate due to epigenetic changes

A

Cells traverse and epigenetic landscape of various differentiation possibility which gradually restricts cell fates

55
Q

What structures are referred to as the building blocks of chromatin

A

Nucleosomes

56
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

57
Q

Which residues are commonly acetylated by histone acetyltransferases

A

Lysine residues

58
Q

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

A

Lysine and arginine

59
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

60
Q

Histone acetyltransferases can modify many different lysine residues, T or F

A

T

61
Q

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

A

F – histone methyltransferase exhibit exquisite site specificities

62
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

63
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

64
Q

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

A

T

65
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

66
Q

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

A

Histone deacetylase and histone demethylase

67
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

68
Q

Lysine acetylation is an indication of what

A

Transcriptionally active genes

69
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

70
Q

How does methylation and acetylation of histone influence transcription

A

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

71
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.

72
Q

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

A

Higher

73
Q

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

A

Bromodomain

74
Q

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

A

PHD finger domains

75
Q

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

A

Transcriptional activators containing PHD fingers

76
Q

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

A

Transcriptional repressors containing bromodomains

77
Q

Transcriptional activators recruit ATP-dependant chromatin remodelling enzymes, what four ways can these enzymes act to upregulate gene transcription

A

Selective histone octamer and whole nucleosome remodelling, selective histone removal and replacement and/or by recruiting code writers and readers

78
Q

In general transcription activators promote RNA polymerase II recruitment, T or F

A

T

79
Q

What ways can transcriptional repressors act to decrease gene transcription

A

Compete for activator binding sites, prevent bound activators from functioning, keep transcriptional activators and transcription machinery away from the start site and also reverse effects of transcriptional activators by creating dense transcriptionally inert chromatin. Finally, they can also recruit enzymes such as histone demethylases and deacetylases as well as methyltransferases

80
Q

Which residue does enhancer of zeste act on and what type of modification is it

A

Enhancer of zeste methylates lysine 27

81
Q

Explain the role of enhancer of zeste in hox gene repression and the involvement of polycomb repressive complexes

A

Enhancer of zeste is the catalytic subunit that acts as part of a complex that represses hox gene expression. PRCs contains chromodomains and methylate lysine 27 loci toproduce global derepression of hox genes

82
Q

As well as histones, DNA can also be modified by methylation. When and how does this occur

A

There is a close functional relationship exists between transcriptionally repressive histone methylation and corresponding DNA methylation on cytosine bases. The addition of methyl groups to cytosine residues is mediated by DNA methyltransferases (DNMTs). Transcriptionally inactive promoters are frequently rich in methylated CpG dinucleotides

83
Q

Explain what is meant by X-chromosome inactivation

A

X-chromosome inactivation is a process that occurs in mammals and acts as a dose compensation mechanism that equalizes the levels of X-chromosome derived gene products in males and females. One X chromosome copy is silenced in each somatic cell during early development of female embryo

84
Q

The X-chromosome copy that is silenced is determined by maternal gene expression in the fertilised oocyte, T or F

A

F - Initial selection of the chromosome for silencing is random

85
Q

How are the progeny of the cell that silences one of the X chromosomes in somatic female cells affected

A

The silencing decision is propagated clonally and all progeny of each cell in which the silencing decision was taken inherit the same silenced X chromosome

86
Q

Explain how X-chromosome inactivation accounts for tortoiseshell or calico cats

A

Calico cats are exclusively female. They are heterozygous for two coat pigment alleles, black and orange. Early in development in progenitor cells either orange or black alleles are inactivated. Where black pigment allele containing X-chromosomes are switched off, all progenitors will produce fur orange in colour. Where orange pigment allele containing X-chromosomes are switched off, all progenitors will produce fur black in colour.

87
Q

Why are regions on the face, neck, bely and white still white in calico cats, despite X-chromosome inactivation

A

These regions don’t contain pigment cells

88
Q

Explain the molecular mechanism of X-chromosome inactivation

A

X-chromosome inactivation involves the synthesis of a non-coding RNA known as Xist from the X-inactivation centre (XIC) on the chromosome destined for inactivation. Xist RNA binds to the X chromosome and acts as a recruitment signal to promote the formation of silent chromatin. This is achieved by recruitment of histone modifying enzymes and other Polycomb Group components and leads to the Histone-3 lysine 27 and H3K9 methylation of core Histones in X chromosome chromatin

89
Q

Explain how H3K27 and H3K9 leads to the formation of a Barr body

A

Lysine 9 and 27 methylation along the entire length of the X chromosome leads to the entire silencing of the chromosome and its shunting to the periphery of the nucleus. This leads to the production of a Barr Body, a highly condensed inactive X chromosome at the periphery of the nucleus of every female somatic cell

BMS242 Cell and Molecular (26 decks)

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