Epigenetics And Chronic Disease Flashcards

1
Q

What does heritability of epi genetics mean

A

At cellular level after differentiation, the cell progeny will have the shared epigentic markers

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2
Q

Where does dna methylation occur

A

C5 on cytosine
Mainly in cpg sites scattered across genome
Hardly ever at cpg islands near promoter

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3
Q

Which dnmt is able to recognise and put back same methylated patterns after replication

A

Dnmt1

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4
Q

Which dnmts allow for new methylation patterns important in early development

A

3a and b

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5
Q

Give 3 examples of when cpg islands would be methylated

A

Gene imprinting eg x silencing

Transposable elements which can cause mutagenesis are suppressed

Tissue specific expression patterns

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6
Q

How 2 ways does it cause repression

A

A cpg site methylated could be part of a tf binding site

More importantly it recruits large protein complexes eg mecp2 mbd which is usually in complex with other repressors like sin3a or HDACs

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7
Q

Fr- where is methylated for tissue specificity

A

Cpg shores 2kb from islands but still alter gene expression

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8
Q

Fr- which enzymes/proteins needed to demethylate cytosine

A

Tet which adds hydroxyl - can be oxidated

ApoBec which deaminates it

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9
Q

What does adding hydroxyl stop binding of

A

Mecp2

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10
Q

Fr - Which 3 readers exist

A

Mbd eg mecp2

UHRF- phd domain and ring finger

Zinc finger proteins

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11
Q

What do mbd have which bind other repressor complexes

A

Txn repressor domains (mutated in Rhett)

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12
Q

What is uhrf important for

A

Guiding dnmt1 to previously methylated after replication

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13
Q

Which histone tail when methylated is only one which is activating

A

K4 h3

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14
Q

Which 2 lysine residues commonly both acetylated and methylated

A

K9h3
K27h3

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15
Q

Which group acetylates lysine’s to remove positive charge

A

HATS
3 subclasses gnat , myst and cbp/p300

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16
Q

Are they in complexes?

A

Yes eg gcn5 and saga

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17
Q

Are HDACs in complex and give examples

A

Yes eg both nurd and sin3a complexes have both HDAC 1 and 2

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18
Q

Which histone residues can be phos

A

Ser,thr,tyr

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19
Q

When are some serine residues phos for condensation

A

Mitosis by aurora B

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20
Q

Which hkmt targets k9h3

A

Suvsr 39

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21
Q

Who methylated arginine residues on histones

A

PRMTs

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22
Q

Does ageing cause changes in Epigenetics

A

Yes

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23
Q

Which Epigenetics patterns can predict biological age

A

Methylation patterns

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24
Q

What can methylation pattern analysis not find

A

Tumour suppressor/key genes.

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25
So what is genome wide analysis important for
Find primary site of tumour to predict best treatment Also determines sensitivity to drugs Also determines subtype of cancer and prognosis
26
What was found in medulloblastoma methylation profiling
4 subclasses, and the 3 with poorer prognosis all had methylation in il8 and mxi1
27
What does cpg methylation of mgmt dna repair enzyme (common in cancers) cause sensitivity to
Alkylating agents like carmustine (chemotherapy)
28
How
Targets the 06 methylguanosine and cross links dna using its binding to this If mgmt is expressed this oncogneuc marker is removed straight away so can’t cross link
29
What is mismatch repair for
Correctly changing mismatched bases during replication to stop mutations
30
What sort of germ line mutations cause mmr deficiencies eg in hereditary crc
Mlh1
31
Why does this gene associate with Epigenetics
It can be hypermethtlsted at 5’ to cause same mmr deficiency
32
Why is this methylation suggested to cause an MSI+ crc phenotype
It causes micro satellite instability as the mutations from mmr deficiency usually occur in micro satellite sequences
33
Why would mlh1 deficiency or methylation reduce the sensitivity to dna damage drugs like cisplarin
They use the fact mmr response would cause apoptosis of the cancer cell when dna damage induced by these drugs. If mmr not possible can’t do it
34
Other than mgmt what other TSG are dna methylated
Brca1 and p14arf
35
Which reversal therapy is a dnmt inhibitor used for myelodyspplastic syndrome survival
Azacitidine
36
What does it do
Increases survival more than conventional therapies Since mds chronic disease is associated with dna methylation
37
Is it known why cancer abnormal methylation occurs
No but it maybe due to increased Epigenetic drift in prolif cells
38
Which hkmt gene mutation occurs commonly
Ezh2
39
What is this mutation associated with
Non-Hodgkin lymphoma (b cell cancer)
40
What does Ezh2 usually do in b cells
Methylates anti proliferation genes like cdkn so that b cells can expand
41
What does the mutation cause
Blocks Ezh2 degradation
42
Which cancers also see Ezh2 increased expression unknown why
Prostate and breast
43
APL leukaemia causes fusion proteins. What do these bind which recruits HDAC complexes
Retinoids acid response elements RARE
44
What do these HDAC complexes do
Repress genes for normal myeloid differentiation and proliferation = promutafenic
45
What can cause ecadherin suppression allowing metastasis eg in breast cancer
HDAC complexes
46
Why are HDACs complicated
More then 70 diff enzymes 4 classes (1,2,4 and sirtuins) Can de acetylate histone proteins but also normal proteins which may also cause cancer eg e2f
47
How can smoking be an example of environmental impacts on Epigenetics
Seen in bronchial epi cells to methylate p16 and dapk (known to suppress cancers) Same pattern seen in lung cancer patients
48
Which dietary nutrient important for methylation of the iap upstream of agouti gene
Folate
49
What happens when low maternal folate in mice
Agouti iap can’t be methylated suppressed any long and agouti gene is expressed. Causes diabetes, obesity and yellow coat
50
Give an example of early life/in uteri exposure having impact on chronic disease susceptibility
Dutch hunger Those in first trimester show levels of obesity, diabetes and heart disease susceptibility
51
What did later exposure correlate with
Smaller birth weight but nothing else
52
What was the first gene seen to be hypometthlated and correlated to the time of the Dutch hunger
Igf2
53
What did gwas later study find
181 differential ly methylated regions in sibling pairs exposed and not exposed
54
Cpt1a was found methylated more in exposed. How does this suggest the heart disease susceptibility
Methylated increases LDL cholesterol levels
55
What does smad7 methylation indicate
Reduced pancreatic b cell function = diabetes?
56
Which fungicide endocrine disruptor can reduce sperm count and motility in 2 mice generations (trans generational inheritance)
Vinclozolin fungicide
57
How did this correlate with methylation
5 differentially methylated genes found in up to 3 mouse generations after f0 was exposed / injected
58
Which chemical found in plastic manufactures eg plastic bottles can affect Epigenetics and reproductive health
BPA
59
Which protein snp needs presence of childhood trauma to dysregulste stress responses via GR and cause issues like ptsd/psychiatric disorders
Fkbp5
60
How does early trauma affect the fkbp5 gene
Demetthlates intron 7 which increases its txn by glucocorticoids binding to their receptor in nucleus
61
Why is increased fkbp5 an issue
It blocks GR activity so causes cortisol/glucocorticoid resistance and impairs the stress response
62
Which HDAC is found to increase longevity in drosophila and mice and c elegans
Sirt1
63
What does this suggest
Maybe reversing epigenefics can reduce chronic disease
64
What does caloric restriction have to do with sirt1
Increases its activation
65
What nutrient pathway is downregulated by CR
Mtor (blocks autophagy)
66
Mouse model of machado Joseph disease (neuropathy) found Cr and what drug reverses symptoms
Resveratrol
67
What does resveratrol do
Increase sirt1 activity
68
What symptoms of machado Joseph did cr/sirt1 help
Increased autophagy via deacetylation of lc3 protein Reduced neuro inflammation via deacetylation of TNFa, il1?b and il6
69
What is resverstrol (a natural phenol) used for now
Anti inflam and anti oxidant via sirt1 deacetylation to protect from diseases like Alzheimer’s, cancer and arthritis (chronic diseases)