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Biochemistry: Gene Expression > Epigenetics > Flashcards

Epigenetics Flashcards

1
Q

What is meant by epigenetics?

A

Heritable modification of the phenotype without change in the genotype

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2
Q

How is cell identify defined?

A

By a unique transcriptional programme which is locked in place by epigenetic modifications

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3
Q

How do a liver and skin cell differ in a mouse?

A

They are all genetically identical but vary in phenotype

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4
Q

Define: genetics

A

Study of genetic material which determines the properties of inheritance and phenotype

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5
Q

Define: epigenetics

A

Study of modifications that alter the phenotype without altering the genotype

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6
Q

All cells from a common precursor share the same genotype. How does a liver cell become a liver cell, and a skin cell become a skin cell?

A

Through a unique transcriptional programme which is locked in place by epigenetic modifications

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7
Q

What is meant by the epigenetic code/ epigenome?

A

The set of epigenetic features that create different phenotypes in different cells

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8
Q

Give two key epigenetic mechanisms

A

1) DNA modifications - methylation

2) Chromatin modification - methylation, acetylation, phosphorylation, ubiquitination

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9
Q

On which residues does DNA methylation occur in:

1) prokaryotes
2) eukaryotes?

A

1) on adenine

2) on cytosine

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10
Q

In general, is DNA methylation reversible?

A

No, generally permanent

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11
Q

What are the two classes of DNA methyl’s enzymes?

A

Dnmt1

Dnmt3a/3b

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12
Q

What type of DNA is recognised by Dnmt1?

A

Hemi-methylated DNA

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13
Q

Which type of DNA methylation is mediated by Dnmt1?

A

After DNA replication

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14
Q

What is the purpose of Dnmt1?

A

Maintains the pattern of methylation through replication

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15
Q

What is the principal role of DNA methylation?

A

To switch off transcription LONG TERM

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16
Q

Why is most of the human genome methylated?

A

To switch off transcription of ‘junk’ DNA - i.e. to maintain genomic stability

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17
Q

What are the two lines of evidence for the importance of DNA methylation in keeping junk DNA silent and maintaining genomic stability?

A

1) 5-azacytidine: cytosine analogue that can’t be methylated. Dilutes DNA methylation through each round of cell division - loss of DNA methylation - activates endogenous retroviruses (i.e junk DNA)
2) Dnmt1 partial KO mice (HYPOMORPH) - develop aggressive T cell tumours due to genomic instability and Trisomy of chromosome 13

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18
Q

What is the difference between Dnmt1 and Dnmt3a/3b?

A

1) replication dependent

2) de novo

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19
Q

What percentage of CpG dinucleotides are methylated in the mammalian genome?

A

More than 50% (most)

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20
Q

How many cytidine residues are methylated in the mammalian genome?

A

3-4%

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21
Q

Cytidine is generally UNDER-represented in the mammalian genome. What does this mean?

A

Often undergoes spontaneous deaminated to thymidine - i.e. amine group is removed

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22
Q

Which residues are methylated in the human genome?

A

Cytidine - in CpG dinucleotides

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23
Q

Around how many CpG dinucleotides are lost due to cytidine under-representation? (i.e. deamination)

A

Most changes repaired: about 3-4 cytidines escape

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24
Q

Where will unmethylated CpGs be found?

A

Near active genes, as methylation is associated with silenced genes

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25
Q

What are CpG islands?

A

UNMETHYLATED CpGs

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26
Q

Where are CpG islands usually located?

A

5’-end of active genes (i.e. upstream)

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27
Q

Generally, how long are the regions containing CpG islands?

A

1-2 kb

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28
Q

What is the content of CpG islands?

A

> 50% CpG content

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29
Q

KEY feature of CpG islands?

A

CpG islands are RESISTANT to DNA methylation

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30
Q

What is the result of DNA methylation?

A

Long-term silencing

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31
Q

What type of genes are often surrounded by CpG islands?

A

House-keeping genes

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32
Q

Why are CpG islands often found by house-keeping genes?

A

Because they are constitutively active

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33
Q

In the course of differentiation, e.g. from stem cell to liver cell, how are other tissue-specific genes switched off?

A

Promoter methylation (e.g. of skin cell genes)

34
Q

At what point will a gene start to be turned off?

A

> 50% methylation

35
Q

How does DNA methylation silence genes?

A

Methyl groups act as binding sites for methylated DNA binding proteins (MBDs)

36
Q

Which are the three main MBDs?

A

Mecp2, MBD2, MBD1

37
Q

What is an MBD?

A

Methylated DNA Binding Proteins/domains

38
Q

What is the NuRD?

A

Nucleosome Remodelling and Deacetylase complex

39
Q

How does NuRD work?

A

MBD2 recognises whether gene is methylated - binds to methylated DNA, then recruits the rest of NuRD. Deacetylase activity of NuRD removes acetyl groups from lysines, which prevents transcription.
Mi2-Beta alters nucleosome positions. Silences transcription.

40
Q

How is 5-methylcytosine changed into 5-HYDROXYmethylcytosine?

A

By TET1/ TET2

41
Q

What are Tet1, Tet2 and Tet3?

A

Enzymes that add a hydroxyl group to the methyl group on cytidine to make 5-hydroxymethylcytosine

42
Q

Where are the Tet enzymes predominantly expressed?

A

Brain and stem cells

43
Q

What is the purpose of Tet enzymes?

A

They prevent recruitment of methyl binding proteins to the DNA

44
Q

What are two proposed theories for the addition of a hydroxyl group to the methyl on 5-methycytosine?

A

1) may prevent binding of methylated-DNA binding proteins

2) stable intermediate in DNA demethylation process

45
Q

What are the TET proteins?

A

Dioxygenases of the Ten-Eleven Translocation family. They are 5-methylcytosine oxidases that convert 5mC to 5hmC

46
Q

Give a possible function of TET2

A

Role in generating iPS cells

47
Q

What is the histone code hypothesis?

A

An epigenetic marking system using different combinations of histone modification patterns to regulate specific and distinct functional outputs of eukaryotic genomes
-i.e. it determines whether a gene is ON, OFF, or may be on in the future

48
Q

How do the following modifications affect transcription:

1) lysine acetylation
2) lysine methylation

A

1) always ON

2) context-dependent; H3K4me3 = ON; H3K27me3 = OFF

49
Q

What are the two different forms of chromatin?

A

Euchromatin and heterochromatin

50
Q

Name 3 PTM histone modifications found in euchromatin

A

1) H3/H4 acetylation
2) H3K4me3
3) H3S10P

51
Q

Name 3 PTM histone modifications found in heterochromatin

A

1) H3K27me3
2) H4K20me3
3) high DNA methylation

52
Q

What charge do histone tails generally carry?

A

Positive due to lysine/arginine rich tails

53
Q

When is Oct-4 inactivated?

A

During stem cell differentiation

54
Q

Where does HDAC deacetylate lysines to repress transcription?

A

On H3K9

55
Q

Where is heterochromatin found?

A 
Centromeres
Telomeres
Repetitive elements
Tissue-specific genes
Intergenic regions
Inactive X chromosomes
56
Q 
What is the effect of the following modifications on transcription:
DNA methylation
H3/H4 acetylation
H3K4me3
H3K27me3
H4K20me3
H3S10P
H3K9me3
A

1) DNA methylation - represses
2) H3/H4 acetylation - activates
3) H3K4me3 - activates
4) H3K227me3 - represses
5) H4K20me3 - represses
6) H3S10P - activates
7) H3K9me3

57
Q

Name 3 modifications associated with active genes (euchromatin)

A

1) H3/H4 acetylation
2) H3K4me3
3) H3S10P

58
Q

Name 3 modifications associated with repressed genes (heterochromatin)

A

1) DNA methylation
2) H3K27me3
3) H4K20me3

59
Q

What does G9a-methylatransferase do?

A

Methylates H3 (H3K9me3)

60
Q

Name two major epigenetic silencing machineries

A

G9a/GLP and Polycomb Repressive Complex 2 (PRC2; active subunit = Ezh2)

61
Q

What is Oct-4?

A

A transcription factor

62
Q

What is Oct-4 primarily responsible for?

A

Maintaining a stem cell as a stem cell

63
Q

What must occur in order for stem cell differentiation to occur?

A

Oct-4 must be switched off

64
Q

In a stem cell, Oct4 must be silenced in order for differentiation to occur. How does this happen?

A

1) transcriptional repressor binds- GCNF (germ cell nuclear factor)
2) repressor recruits HDAC - removes acetyl groups
3) gene repressed
4) ensure Oct-4 off permanently:
5) G9a methylates H3K9 (‘OFF’ mark)
6) H3K9me3 adds as recognition site for HP1 (heterochromatin protein 1)
7) HP1 recruits Dnmt3a/3b (DNA methytransferase 3a/3b)
8) Dnmt3a/3b methylates DNA

65
Q

Once G9a has methylated H3K9, what happens?

A

H3K9me3 is recognised by HP1

66
Q

What is HP1?

A

Heterochromatin Protein 1

67
Q

How is HP1 recruited to DNA?

A

Recognises H3K9me3

68
Q

How is Dnmt3a/3b recruited to the Oct-4 gene to allow methylation and subsequent silencing of Oct-4 to allow differentiation of stem cells?

A

It is recruited to H3K9me3 DNA via HP1

69
Q

What is the first step of stem cell differentiation?

A

Binding of the transcriptional repressor GCNF, which recruits HDAC, which represses genes

70
Q

What technique has been used to monitor histone modifications across the genome?

A

ChIP-seq

71
Q

What is unique about some embryonic stem cell genes?

A

They are BIVALENT: they are poised, having a combination of off and on signals

72
Q

What is ChIP-seq?

A

Chromatin immunoprecipitation to isolate the proteins bound to specific regions of DNA coupled to DNA sequencing to identify these regions

73
Q

Name two powerful tools to identify genome-wide profiles of transcription factors, histone modifications, DNA methylation, and nucleosome positioning

A

ChIP-chip (ChIP followed by hybridisation to microarrays)

ChIP-seq (ChIP followed by high-throughput sequencing)

74
Q

What makes ChIP-seq better than ChIP-chip?

A

It requires less DNA input, has expanded dynamic range, and is compatible with sample multiplexing

75
Q

What happens to the genome in cancer?

A

Global genomic HYPOmethylation

76
Q

How are TSGs silenced in cancer?

A

OCCASIONAL methylation of CpG Islands, e.g. in the promoter for the genes for p16INK4a and p14ARF (lead to dysregulation of the cell cycle)

77
Q

What epigenetic marks do tumours lose?

A

H4K16Ac, and H4K20me3

78
Q

Give two examples of diseases in which genomes are globally hypomethylated

A

1) cancer

2) autoimmune diseases, e.g. rheumatoid arthritis

79
Q

Almost every disease type will have an epigenetic change. Give some examples

A

cancer, autoimmune diseases such as rheumatoid arthritis

80
Q

What is the consequence of DNA demethylation?

A

Expression of junk DNA; increased plasticity of the genome

81
Q

Give an example of drugs that target class I HDACs to treat certain cancers such as cutaneous T-cell lymphoma

A

SAHA
Romidepsin
Belinostat

Biochemistry: Gene Expression (8 decks)

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