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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?

21
Q

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

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
Wat does chIP involve in the detection of histone modifications? (3 things it is used for)
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
What does ChIp stand for?
- Chromatin ImmunoPrecipitation combined with high throughput Sequencing
27
What is ENCODE?
- ENCyclopedia Of DNA Elements | - Whole genome approach for a map of human genome activity
28
What kinds of histone modifications are involved in human disease and which types of diseases are these?
- 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
What is involved in DNA methylation?
- 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
What % of CpG sites are Ch3’d (methylated) in humans?
70%
31
Where are CpG rich regions found?
- “islands” - Found UPSTREAM of lots of human promoters and generally HYPOMETHYLATED - Methylation status at CpG islands correlates with GENE EXPRESSION
32
Are DNA methylation sites tissue specific?
- YES!
33
Can DNA methylation play a role in cancer?
- YES | - e.g. De novo mehtylation can occur in cancer cells--> gene silencing --> early events in tumorigenesis
34
What are the two different methods for detecting DNA methylation?
- MeDIP (methylation dependent immunoprecipitation) | - bisulfite treatment
35
What does MeDIp involve in the detection for DNA methylation?
- Igs SPECIFIC for methyl cytosine | - Allows for the QUANTIFICATION of DNA methylation (RELATIVE QUANTIFICATION)
36
Which two pathways can you use for the detection og DNA methylation through MeDIP?
- Array hybridization and high throughput screening
37
What does the bisulfite treatment involve in terms of detection of DNA methylation?
- 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
What is the process for EWAS (epigenome Wide association study)?
- 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
How is EWAS involved in cancer?
- 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
Which pathways are the KEY to DNA methylation instability?
- Chromatin remodelling and Wnt signalling pathways
41
What are the limitations of EWAS in complex diseases ?
- 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
What role does DNA methylation have in complex diseases?
High variability observed: o In different individuals o In different tissues o At different timepoints (age--> different methylation profiles with different age)
43
What occurs in DNA methylation with relation to imprinting?
- 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
Are imprinted alleles usually HEAVILY METHYLATED?
-YES--> They have chromatin or histone modifications -->“epigenetic changes”
45
What is an example of imprinting (silencing) having different phenotypes?
- Prader-Willi syndrome--> Expressed form paternal copy (amternal silecned) - Angelman syndrome--> Expressed from maternal copy (paternal silenced)
46
What are 6 characterisitcs of miRNA?
- 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
What are 6 characterisitcs of siRNA?
- 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
What do miRNAs play a role in (in humans)?
- The immune system and disease (e.g. IBD)
49
Which processes are long coding RNAs involved in?
- gene specific transcription - Imprinting - X-chromosome inactivation

BMS2042 (11 decks)

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