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Chronic Disease > Epigenetics And Chronic Disease > Flashcards

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
Q

So what is genome wide analysis important for

A

Find primary site of tumour to predict best treatment

Also determines sensitivity to drugs

Also determines subtype of cancer and prognosis

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26
Q

What was found in medulloblastoma methylation profiling

A

4 subclasses, and the 3 with poorer prognosis all had methylation in il8 and mxi1

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27
Q

What does cpg methylation of mgmt dna repair enzyme (common in cancers) cause sensitivity to

A

Alkylating agents like carmustine (chemotherapy)

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28
Q

How

A

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
Q

What is mismatch repair for

A

Correctly changing mismatched bases during replication to stop mutations

30
Q

What sort of germ line mutations cause mmr deficiencies eg in hereditary crc

A

Mlh1

31
Q

Why does this gene associate with Epigenetics

A

It can be hypermethtlsted at 5’ to cause same mmr deficiency

32
Q

Why is this methylation suggested to cause an MSI+ crc phenotype

A

It causes micro satellite instability as the mutations from mmr deficiency usually occur in micro satellite sequences

33
Q

Why would mlh1 deficiency or methylation reduce the sensitivity to dna damage drugs like cisplarin

A

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
Q

Other than mgmt what other TSG are dna methylated

A

Brca1 and p14arf

35
Q

Which reversal therapy is a dnmt inhibitor used for myelodyspplastic syndrome survival

A

Azacitidine

36
Q

What does it do

A

Increases survival more than conventional therapies

Since mds chronic disease is associated with dna methylation

37
Q

Is it known why cancer abnormal methylation occurs

A

No but it maybe due to increased Epigenetic drift in prolif cells

38
Q

Which hkmt gene mutation occurs commonly

A

Ezh2

39
Q

What is this mutation associated with

A

Non-Hodgkin lymphoma (b cell cancer)

40
Q

What does Ezh2 usually do in b cells

A

Methylates anti proliferation genes like cdkn so that b cells can expand

41
Q

What does the mutation cause

A

Blocks Ezh2 degradation

42
Q

Which cancers also see Ezh2 increased expression unknown why

A

Prostate and breast

43
Q

APL leukaemia causes fusion proteins. What do these bind which recruits HDAC complexes

A

Retinoids acid response elements RARE

44
Q

What do these HDAC complexes do

A

Repress genes for normal myeloid differentiation and proliferation = promutafenic

45
Q

What can cause ecadherin suppression allowing metastasis eg in breast cancer

A

HDAC complexes

46
Q

Why are HDACs complicated

A

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
Q

How can smoking be an example of environmental impacts on Epigenetics

A

Seen in bronchial epi cells to methylate p16 and dapk (known to suppress cancers)

Same pattern seen in lung cancer patients

48
Q

Which dietary nutrient important for methylation of the iap upstream of agouti gene

A

Folate

49
Q

What happens when low maternal folate in mice

A

Agouti iap can’t be methylated suppressed any long and agouti gene is expressed. Causes diabetes, obesity and yellow coat

50
Q

Give an example of early life/in uteri exposure having impact on chronic disease susceptibility

A

Dutch hunger
Those in first trimester show levels of obesity, diabetes and heart disease susceptibility

51
Q

What did later exposure correlate with

A

Smaller birth weight but nothing else

52
Q

What was the first gene seen to be hypometthlated and correlated to the time of the Dutch hunger

A

Igf2

53
Q

What did gwas later study find

A

181 differential ly methylated regions in sibling pairs exposed and not exposed

54
Q

Cpt1a was found methylated more in exposed. How does this suggest the heart disease susceptibility

A

Methylated increases LDL cholesterol levels

55
Q

What does smad7 methylation indicate

A

Reduced pancreatic b cell function = diabetes?

56
Q

Which fungicide endocrine disruptor can reduce sperm count and motility in 2 mice generations (trans generational inheritance)

A

Vinclozolin fungicide

57
Q

How did this correlate with methylation

A

5 differentially methylated genes found in up to 3 mouse generations after f0 was exposed / injected

58
Q

Which chemical found in plastic manufactures eg plastic bottles can affect Epigenetics and reproductive health

A

BPA

59
Q

Which protein snp needs presence of childhood trauma to dysregulste stress responses via GR and cause issues like ptsd/psychiatric disorders

A

Fkbp5

60
Q

How does early trauma affect the fkbp5 gene

A

Demetthlates intron 7 which increases its txn by glucocorticoids binding to their receptor in nucleus

61
Q

Why is increased fkbp5 an issue

A

It blocks GR activity so causes cortisol/glucocorticoid resistance and impairs the stress response

62
Q

Which HDAC is found to increase longevity in drosophila and mice and c elegans

A

Sirt1

63
Q

What does this suggest

A

Maybe reversing epigenefics can reduce chronic disease

64
Q

What does caloric restriction have to do with sirt1

A

Increases its activation

65
Q

What nutrient pathway is downregulated by CR

A

Mtor (blocks autophagy)

66
Q

Mouse model of machado Joseph disease (neuropathy) found Cr and what drug reverses symptoms

A

Resveratrol

67
Q

What does resveratrol do

A

Increase sirt1 activity

68
Q

What symptoms of machado Joseph did cr/sirt1 help

A

Increased autophagy via deacetylation of lc3 protein
Reduced neuro inflammation via deacetylation of TNFa, il1?b and il6

69
Q

What is resverstrol (a natural phenol) used for now

A

Anti inflam and anti oxidant via sirt1 deacetylation to protect from diseases like Alzheimer’s, cancer and arthritis (chronic diseases)

Chronic Disease (16 decks)

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