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BMS2042 > WEEK 9: COMPLEX DISEASES II EPIGENETICS > Flashcards

WEEK 9: COMPLEX DISEASES II EPIGENETICS Flashcards

1
Q

What can epigenetic mehcanisms be affected by?

A
  • Development (in utero, childhod)
  • Environmental chemicals
  • Drugs/pharmaceuticals
  • Aging
  • Diet
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2
Q

In histone modification, where do the epigenetic factors bind to?

A
  • The histone tails
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3
Q

What are the health endpoints of epigenetic mechanisms?

A
  • Cancer
  • Autoimmune disease
  • Mental disorders
  • Diabetes
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4
Q

What do actively transcribed genes carry high levels of?

A
  • Active modifications such as acetylations and methylation
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5
Q

What does genome wide chromatin accessibility suggest in terms of cancer?

A
  • Suggests molecular mechanisms for cancer associated inherited variants and somatic mutations in the NON CODING genome
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6
Q

What effect does increased DNA methylation have on tumour suppressor genes?

A
  • It turns them OFF
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7
Q

What effect does decreased DNA methylation have on Oncogenes?

A
  • Turns them ON
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8
Q

What is imprinting in complex diseases confounded by?

A
  • Environmental factors
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9
Q

What are miRNAs involved in?

A
  • Multiple important roles in gene regualtion (development) and implicated in some cancers
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10
Q

What are endogenous short interfering RNA (endo siENA) incolved in ?

A
  • Derived from pseudogenes , inverted repeats etx\c. and involved in gene regulation in somatic cells and in regulating some types of transposon
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11
Q

What are long non coding RNAs involved in?

A
  • Regulating gene expression

- Monoallelic expression (X-inactivation, imprinting) and/or has antisense regulators

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12
Q

What is involved in the RNAi mechanism?

A
  • Ds RNA binds to the protein DICER
  • This CLEAVES dsRNA into smaller fragments
  • One of the RNA strands is loaded onto a RISC complex
  • Links the complex to the mRNA strand by basepairing
  • mRNA is cleaved and destroyed –> no protein can be synthesised
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13
Q

What is epigenetics?

A
  • Any modification NOT directly related to DNA sequence

- Epi= “on top of” or “in addition to” DNA sequence and traditional inheritance

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14
Q

Are all epigenetic changes heritable?

A
  • NO

- can also be from environment

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15
Q

Heterochromatin has ____ levels of methylation and ____ levels of acetylation

A
  • Higher levels of methylation and lower levels of acetylation
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16
Q

Eurochromatin has _____ levels of metylation and _____ levels of acetylaton.

A
  • Lower levels of methylation and higher levels of acetylation
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17
Q

What are 3 examples of histone modifications?

A
  • Acetylation
  • Methylation
  • Phosphorylation
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18
Q

Can more than one histone modification occur at same time?

A

-YES

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19
Q

Why is residue H3K9 important?

A

-Because it contains 3PTMs!!!  trimethylation (Constitutive heterochromatin), Dimethylation (Faculatative heterochromatin), Acetlyation (Euchromatin)

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20
Q

Can histone modifications have strong effects on mRNA transcription/expression?

A
  • YES
21
Q

Can different histone modifications at the same residue have opposite effects?

A
  • YES
22
Q

What are the histone modification detection methods used to identify?

A
  • Used to identify DNA sequences associated with histone and other modifications resulting from INCREASED DNA accessibility (bc. actively transcribed) + can be applied to SCREENING the WHOLE GENOME
23
Q

What are the two methods for detecting histone modifications?

A
  • DHS (DNase I Hypersensitive Assay)

- cHIp (chromatin immunoprecipitation)

24
Q

What does DHS invovle in detection of histone modifications?

A
  • Crossliniking TFs to DNase
  • Transcriptional activity in areas that are open/prone to degradation by DNase
  • Used to mark regulation sites
  • (Not really used anymore)
25
Q

Wat does chIP involve in the detection of histone modifications? (3 things it is used for)

A
  1. Used to identify TFs bound to SPECIFIC DNA sequence motifs
  2. Used to characterize DNA sequence motifs recognised by TFs
  3. Used to study the EFFECT of polymorphisms (SNPs)
    - It is immunoprecipitation combined with high throughput screening
    - It identifies locations in the genome BOUND BY PROTEINS
26
Q

What does ChIp stand for?

A
  • Chromatin ImmunoPrecipitation combined with high throughput Sequencing
27
Q

What is ENCODE?

A
  • ENCyclopedia Of DNA Elements

- Whole genome approach for a map of human genome activity

28
Q

What kinds of histone modifications are involved in human disease and which types of diseases are these?

A
  • Mutations in histone acetyl trasnferases HAT and protein methyltransferases PMT
  • Only in RARE SEVERE CONDITIONS
    e. g. MLL gene in Myeloid or Mixed -lineage leukemia  chromosomal rearrangements (infant, pediatric, adult and therapy induced acute leukemia)
29
Q

What is involved in DNA methylation?

A
  • Addition of a CH3 group to C5 of a Cytosine residue –> from the action of DNA methyl transferases (DNMTs)
  • Taking place at level of Cytosines followed by Guanine base–> CpG di nucleotides
30
Q

What % of CpG sites are Ch3’d (methylated) in humans?

A

70%

31
Q

Where are CpG rich regions found?

A
  • “islands”
  • Found UPSTREAM of lots of human promoters and generally HYPOMETHYLATED
  • Methylation status at CpG islands correlates with GENE EXPRESSION
32
Q

Are DNA methylation sites tissue specific?

A
  • YES!
33
Q

Can DNA methylation play a role in cancer?

A
  • YES

- e.g. De novo mehtylation can occur in cancer cells–> gene silencing –> early events in tumorigenesis

34
Q

What are the two different methods for detecting DNA methylation?

A
  • MeDIP (methylation dependent immunoprecipitation)

- bisulfite treatment

35
Q

What does MeDIp involve in the detection for DNA methylation?

A
  • Igs SPECIFIC for methyl cytosine

- Allows for the QUANTIFICATION of DNA methylation (RELATIVE QUANTIFICATION)

36
Q

Which two pathways can you use for the detection og DNA methylation through MeDIP?

A
  • Array hybridization and high throughput screening
37
Q

What does the bisulfite treatment involve in terms of detection of DNA methylation?

A
  • DNA treated with sodium bisulfite
  • Causes ONLY unmethylated CYTOSINES to convert to URACIL
  • Sequencing then reveals where the methylated cytosines remain in the genome
38
Q

What is the process for EWAS (epigenome Wide association study)?

A
  • Recruit cases and controls into study (aim for whole (epi) genome analyses)
  • Select tissue of interest
  • Extract, quantify, QC DNA
  • Sodium bisulfite treatment
  • From this can EITHER hybridise to microarrays OR detect by NGS (next generation sequencing)
39
Q

How is EWAS involved in cancer?

A
  • Took 6010 tumour samples from 23 DIFFERENT cancer types (TCGA)
  • Identified aberrant DNA methylation and associated changes in RNA expression
  • Has a pan cancer amp of aberrant DNA methylation to inform therapeutic studies
40
Q

Which pathways are the KEY to DNA methylation instability?

A
  • Chromatin remodelling and Wnt signalling pathways
41
Q

What are the limitations of EWAS in complex diseases ?

A
  • It is reversible –>unstable changes
  • Quantitative (small) differences
  • Tissue heterogeneity/composition
  • Genotype-dependent effects
  • E.g. people who smoke have changes in DNA methylation patterns compared to smokers who quit –>BUT not all black and white…complex
42
Q

What role does DNA methylation have in complex diseases?

A

High variability observed:
o In different individuals
o In different tissues
o At different timepoints (age–> different methylation profiles with different age)

43
Q

What occurs in DNA methylation with relation to imprinting?

A
  • One allele is transcriptionally INACTIVE (silenced) depending on the parent it was inherited from
  • Selective gene expression impacts on the phenotypic expression
  • Silencing takes place in early development and is transmitted across generations –> “reprogramming”
44
Q

Are imprinted alleles usually HEAVILY METHYLATED?

A

-YES–> They have chromatin or histone modifications –>“epigenetic changes”

45
Q

What is an example of imprinting (silencing) having different phenotypes?

A
  • Prader-Willi syndrome–> Expressed form paternal copy (amternal silecned)
  • Angelman syndrome–> Expressed from maternal copy (paternal silenced)
46
Q

What are 6 characterisitcs of miRNA?

A
  • found in animals and plants
  • from endogenous genes
  • Ss, stem loop structure
  • Partial match with target genes (3’UTR)
  • Often MUTLIPLE targets
  • INHIBITION of translation
47
Q

What are 6 characterisitcs of siRNA?

A
  • found in LOWER animals and plants
  • From Exogenous genes (i.e. viruses + endo-siRNAs)
  • Double stranded
  • PERFECT match with target genes
  • Usually ONE target (same gene)
  • mRNA cleavage
48
Q

What do miRNAs play a role in (in humans)?

A
  • The immune system and disease (e.g. IBD)
49
Q

Which processes are long coding RNAs involved in?

A
  • gene specific transcription
  • Imprinting
  • X-chromosome inactivation

BMS2042 (11 decks)

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