Lecture 3 - Epigenetics Flashcards

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1
Q

Purpose of Epigenetics

A

-Expanding the capacity of the Genome to create diversity

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2
Q

What is Epigenetics

A

-study of Heritable mechanisms that alter gene expression which is not explained by DNA sequence

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3
Q

Epigenome?

A

-Between Genome and Phenotype

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4
Q

Major Mechanism

A

Transcriptional:

  • > DNA Methylation
  • > Chromatin Remodelling

Post Transcriptional:

  • > miRNA
  • > IncRNA
  • > RNAi

Post Translational:
->Histone Modification (then affects transcriptional

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5
Q

DNA Methylation enzymes

A
  • DNTM1: maintaince Methyltransferase

- DNTM3A + B : de novo methyltransferase -> highly expressed at embryo

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6
Q

How to make Hetereochromatin

A
  • Methylation + Methyl-CpG-BP (recruiter) –> Silience DNA

- Histone Deacetylase + Remodelling Proteins –> hetereochromatin

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7
Q

Patterns of Methylation

A

CpG in Promotor -> methylation siliences gene

CpG Island shore -> Inhibition of transcription of gene

Gene Body -> normally methylated (role in optimal trans)

Repetitive Sequences -> inhibits trans of retroviral origin

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8
Q

Consequences of DNA Methylation

A
  • Hypometh of Promotor -> Genome instability
  • Hypermeth of Promotor -> siliences (TSG = CANCER)
  • Deamination of 5-methycyt -> thymidine
  • UV -> thymidine dimers
  • binding site for carcinogens
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9
Q

Which Histone is mainly affected

A

-H3 is mainly affected:

> by adding to R-group of lysines of the N-terminal

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10
Q

Type of Histone Modification

A

> Acetylation - gene expression
Methyl - gene siliencing
Phospho: + mitosis + Meiosis

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11
Q

Histone Code Hypothesis

A

-different combinations of Histone modification, especially located near/in promotor may be very specific to the transcriptional state of that gene

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12
Q

RNAi

A

-RNA Interference
> Gene inactivation:
- both of specific genes + endogenous viruses/transposons/exogenous retrovirus

> directly interferes with mRNA coming out the nucleus going to get translated

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13
Q

Type of RNAi

A

siRNA:

  • db: 21-23 NT with a TT3 overhang
  • form complex with RISC and degrades the mRNA
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14
Q

miR

A

-20-23 NT long
act via:
1) Interact with 3’UTR of mRNA -> attenuates Translation

2) Lead to direct mRNA degradation

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15
Q

What do microRNA and siRNA need?

A

DICER

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16
Q

XIST

A

X-inacive-specific Transcript

  • 17kb spliced non-coding RNA
  • stable expression only in inactive X
  • required to initiate siliencing
17
Q

How is XIST formed

A

-X-inactivation begins when XIC locus synthesises -> XIST –> condenses chromosome whence it came from

18
Q

Types of X-chromosome Inactivation

A
  • Random: both normal + mutation product made
  • Skewed: where 80% of pattern is domination by one of the Xs

-Fortunate Skewed:
> makes mostly normal product

-Unfortunate Skewed:
> makes mostly mutation product

19
Q

X-inactivation and Autoimmune Risk

A

-skewed Inactivation in the Thymus during embryonic life –> most cells exposed to Father/Mother’s X –> after Parturition the T-cells recofnise cell sof the body with opposing X

20
Q

Genomic Imprinting Definition

A

-non-equivalent expression of genes based on parent of origin

21
Q

What is Genomic Imprinting

A
  • for small portion of genes (<1%) -> Only one allelle is expressed the other is shut off
  • which allelle is shut off is dictated by Parent-of-origin
  • IGF2 -> allele is only expressed from father
22
Q

Why is Genomic Imprinting a problem

A

-not usually a problem -> only if the expressed gene is mutated (Prader-willi and Angelman)

23
Q

Cause of Prader-Willi Syndrome

A
  • Maternal UPD
  • Paternal deletion of 15q11-13
  • Wrong imprting
24
Q

Cause of Angelman syndrome

A
  • Paternal UPD
  • Maternal deletion 15q11-13
  • wrong imprinting
  • UBE3A mutation
25
Q

Cancer in Epigenetics

A
  • Imprinting is metastable
  • LOI - loss of original Imprinting

-abnormal imprting of:
> Growth promoting genes ->oncoges -> cancer
> Growth siliencing genes -> TSG -> cancer

26
Q

Position effect

A

-epigenetic effect on gene expression that occurs when location of gene has changed (usually transcribed)

-in DROSPHILIA:
> translocated gene for eye-colour is close to heterochromatin -> heterochromatin spreads and switchs off expression in certain portions of the eye