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Epigenetic Mechanisms in Cancer Flashcards

1
Q

Define genetics

A

The study of the genetic material which determine the properties of inheritance and phenotype

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2
Q

Define epigenetics

A

The study of modifications that alter phenotype without altering the genotype

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3
Q

If there is low DNA methylation and histone acetylation, is the gene turned on or off?

A

On

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4
Q

If there is high DNA methylation and H3-K27me3, is the gene turned on or off?

A

Off

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5
Q

If there is low DNA methylation and histone acetylation, is the the gene turned on or off?

A

On

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6
Q

What is the best described epigenetic mechanism?

A

DNA methylation at CpG dinucleotides

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7
Q

What is DNA methylation regulated by?

A

Dnmt1

Dnmt3a/3b

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8
Q

All cells in a organism are genetically identical so why can’t liver cells for example become stem cells again, or skin cells?

A

Due to cell identity

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9
Q

Define cell identity

A

A unique transcriptional programme which is locked into place by epigenetic modifications

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10
Q

There is parallel usage of the terms epigenome and epigenetic code, but what are these terms used to describe?

A

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

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11
Q

Are epigenetics heritable?

A

Yes over rounds of cell division and sometimes transgenerationally

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12
Q

In the context of epigenetics, what does epi- imply?

A

Features that are ‘on top of’ or ‘in addition to’ genetics

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13
Q

How can DNA be epigenetically modified?

A

By methylation

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14
Q

How can chromatin be epigenetically modified?

A 
By:
Phosphorylation
Acetylation
Methylation
Ubiquitination
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15
Q

Where does DNA methylation occur in prokaryotes?

A

On adenine residues

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16
Q

Where does DNA methylation occur in eukaryotes?

A

On cytosine residues

Only at CpG dinucleotides

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17
Q

What is the principle role of DNA methylation?

A

To switch off transcription long-term

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18
Q

What are the two different kinds of DNA methyltransferase?

A

Replication dependent: Dnmt1

De novo: Dnmt3a/3b

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19
Q

What does DNA methylation maintain?

A

Genomic stability of transposons, endogenous retroviruses, repetitive elements etc.

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20
Q

What does DNA methylation do to junk DNA?

A

It keeps the junk DNA quiet

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21
Q

How does the cytosine analogue 5-azacytidine act as evidence that DNA methylation maintains genomic instability?

A

It cannot be methylated and when added to cells it dilutes DNA methylation through each round of cell division. Loss of DNA methylation leads to reactivation of endogenous retroviruses

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22
Q

How do Dnmt1 knockout mice act as evidence that DNA methylation maintains genomic instability?

A

Mice containing a mutation in the Dnmt1 gene retain only 10% of normal activity and develop aggressive T cell tumours due to trisomy of chromosome 15

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23
Q

Which is a common trait of cancer cells, hypermethylation or hypomethylation of DNA?

A

Hypomethylation

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24
Q

How does DNA methylation lead to long-term silencing?

A

It functions by recruiting histone modifying enzymes

25
In which cell types does the conversion of 5-methyl cytosine to 5-hydroxymethyl cytosine predominantly happen?
In the brain and stem cells
26
DNA demethylation does NOT generally occur in mammalian cells. Give one of the very few specific exceptions to this rule
Except in embryonic development
27
What are the two theories for why 5-methyl cytosine is converted to 5-hydroxymethyl cytosine?
Theory 1: the product prevents the binding of methylated-DNA binding proteins Theory 2: the product is a stable intermediate in the DNA demethylation process
28
What are histone tails thought to interact with?
The PO4- backbone of DNA
29
How is the eukaryotic genome packaged?
Into chromatin
30
Describe the transcriptional status of relaxed and condensed chromatin
Relaxed is transcriptionally active | Condensed is transcriptionally silent
31
Describe the structure of a histone molecule
Have a globular domain and an unstructured, long N-terminal tail rich in Lys+ and Arg+
32
Describe the structure of a nucleosome
147 base pairs of DNA wrapped twice around a histone octamer
33
What type of polymer is a histone?
``` An octamer consisting of 8 monomers 2x H2A 2x H2B 2x H3 2x H4 ```
34
What is the histone code hypothesis?
Histone modifications associated with a gene predict whether a gene is on, off, or might be on at sometime in the future
35
What does Lys acetylation in a histone tail suggest about the transcription status of the gene?
The gene is always on
36
What does Lys methylation in a histone tail suggest about the transcription status of the gene?
It is context dependent
37
What does Lys methylation of H3K4 in a histone tail suggest about the transcription status of the gene?
It is on
38
What does Lys methylation of H3K27 in a histone tail suggest about the transcription status of the gene?
It is off
39
What does a healthy epigenome suggest about the genome?
That it is healthy
40
Where might DNA methylation be low?
Where there is euchromatin
41
Where might DNA methylation be high?
Where there is heterochromatin
42
What has ChIP-seq been used to monitor in respect to epigenetics?
Histone modifications
43
What families can post-translational modifications be sorted into?
Readers, writers, erasers
44
Where is euchromatin found?
Active genes | Recombination sites
45
Where is heterochromatin found?
``` Centromeres Telomeres Repetitive elements Tissue specific genes Intergenic regions Inactive X-chromosomes ```
46
What is ChIP-Seq?
ChIP and next generation sequencing
47
What is the ENCODE project?
The encyclopedia of DNA elements
48
How many data sets are there in the ENCODE project?
1640
49
How many different cell types are there in the ENCODE project?
147
50
There are a number of different DNA-binding proteins and a number of RNA polymerase components in 72 cell types using ChIP-Seq. How many are there?
119
51
How is epigenetics altered in cancer?
Massive global genomic hypomethylation Transcriptional silencing of tumour suppressor genes by CpG island promoter hypermethylation, e.g. p16INK4a, p14ARF etc. Human tumours undergo an overall loss of H4K16Ac and H4K20me3
52
What are patients with germline mutations in DNMT3b-ICF known to have?
Numerous chromosome aberrations
53
What does ICF stand for?
Immunodeficiency-centromeric region instability-facial anomalies
54
Give examples of classical autoimmune diseases that are characterised by massive genomic hypomethylation
Systemic lupus erythematosus | Rheumatoid arthritis
55
Most human disease have an epigenetic cause. What happens to the perfect control of our cells by DNA methylation, histone modifications, chromatin-remodelling and microRNAs in sick cells?
The control becomes dramatically distorted
56
What are tumour suppressors inactivated by?
DNA hyper-methylation
57
Histone modifications are often described as epigenetic, but what might they just reflect?
Transcription
58
Summarise the significant alterations to the epigenome in cancer cells
Global genomic hypomethylation with hypermethylation of tumour suppressor promoters, e.g. p16

Cancer Lectures (24 decks)

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