09: Epigenetics

Question 1

What is epigenetics?

Answer 1

Changes that occur to DNA that do not involve the nucleotide sequence itself but still impact the DNA’s ability to be transcribed.

Modifications of DNA and chromatin that set up stable patterns of gene expression; faithfully transmitted in somatic cells, but reversible in gametogenesis.

Include X-inactivation and genomic imprinting.

Aberrant modifications (epimutations) can cause developmental disorders and cancers.

Question 2

What happens on a molecular level?

Answer 2

• Methylation in a promoter region causes DNA silencing (muting).
  
  • Occurs at CpG islands
  • Mediated by proteins that interact with methyl-CpG and modify chromatin to exclude transcriptional activators.
  • DNA methyltransferase ensures daughter strands are methylated as well (heritable silencing)
• Acetylation in a promoter region causes increased DNA expression (activation).

Question 3

For X-inactivation, explain:

1. Why?
2. How?

Answer 3

1. Females have too much genetic material (X chromosome much larger than Y chromosome); gene balancing necessary.
2. Most of inactive X-chromosome is methylated (Barr body) and histones hypoacytylated, except a few genes, one of which is Xist, which is expressed and serves to help shut down the rest of the chromosome.

Question 4

What is Rett Syndrome?

Answer 4

• X-linked neurological/cognitive disorder seen only in girls.
• Mutation of MeCP2.
• Lethal in males (MeCP2 duplications cause a form of autism in males).
• Although phenotypic resuce of females occurs early in development, it fails subsequently: mature neurons with the adverse pattern of X-inactivation cannot be replaced.

Question 5

What is the genetic utility of imprinting?

Answer 5

For a few genes (~100) scattered throughout the genome, to have the correct amount of protein, either the maternal or paternal copy of the gene needs to be inactivated.

Question 6

What is the Haig Hypothesis?

Answer 6

States that there is a conflict between maternal and paternal drives for reproductive success, thus regulating the allocation of maternal resources.

Question 7

What is Beckwith-Wiedemann Syndrome, and what is its genetic basis?

Answer 7

An epigenetic disesae of gigantism, abnormal kidney and adrenal, hemihypertrophy, childhood tumors (~7%).

Results from an epimutation at either the 5’ of H19 (gain of methylation) or in an intron of the KCNQ1 gene (loss of methylation).

Maternal copy of gene IGF2 (growth) on. (Only paternal copy should be on.)

Question 8

What is Russell-Silver syndrome, and what is its genetic basis?

Answer 8

Severe intrauterine growth restriction (IUGR), due to altered IGF2/H19 imprinting on chromosome 11.

Paternal copy of gene IGF2 (growth) is off (normally on).

This is an epimutation; sequence is unaffected.

Question 9

What is the epigenetic basis of Angelman Syndrome?

Answer 9

Micro-deletion of the Angelman gene on maternal chromosome 15 during maternal oogenesis.

Leads to complete loss of gene function because it is already normally turned off in paternal chromosome.

Question 10

What is the epigenetic basis of Prader-Willi Syndrome?

Answer 10

Micro-deletion of the Prader-Willi gene on paternal chromosome 15 during paternal spermatogenesis.

Leads to complete loss of gene function because it is already normally turned off in the mother.

Note: 28% of PWS is caused by maternal UPD.

Question 11

According to the Haig Hypothesis, what genes are supposed to be imprinted and by which parent?

Answer 11

Gene IGF2 (growth):
Maternal: OFF
Paternal: ON

Gene H19 (anti-growth):
Maternal: ON
Paternal: OFF

Question 12

What occurs in an epimutation? What syndromes arise from epimutations?

Answer 12

Imprinting does not occur when it is supposed to (OFF genes turned ON).

Beckwith-Weidemann (IGF2 on in mother) and Russell-Silver (H19 on in father).

Question 13

How can DNA de-methylation be promoted? Prevented?

Answer 13

Promotes de-methylation: 5aza-dC (DAC); extends survival in pancreatic ductal adenocarcinoma (PDAC) by inducing STAT1; late-stage Rx

Prevents de-methylation: folic acid, vitamin B12, betaine; prevents gastric cancer; early chemoprevention