Epigenetics - Biochemistry - Medbullets Step 1

Overview

Changes in gene expression caused by mechanisms other than changes in actual DNA sequence
Examples
- X-inactivation
- imprinting
- histone modification
  - see Chromatin structure topic

X-inactivation

Overview
- normalizes the genetic amount of males and females (lyonization)
- inactivates # of X chromosomes - 1 in a Barr body
  - triploid X will have 2 Barr bodies
Mechanism
- mediated by XIST gene
- inactivation through methylation
- occurs at blastocyst stage in female embryos
- X copy chosen for inactivation is random
  - after choosing every subsequent cell will have the same X copy inactivated
Clinical relevance
- mosaicism
  - non-homogenous X inactivation
  - some cells express paternal X and some cells express maternal X

Imprinting

Overview
- describes differences in transcriptional activity based on whether the chromosome is of maternal or paternal origin
- at a single locus
  - 1 allele is active
  - 1 allele is inactive
- creates a hemizygous state
Mechanism
- inactive ("imprinted") allele is methylated during gametogenesis
  - creates transcriptional inactivity
- is maternal/paternal specific
  - gene at one locus always methylated on a specific copy
- all cells of an individual have same imprinting level
- during gametogenesis of the individual the methylation state is erased
  - reset to be either maternal or paternal depending on the sex
Clinical importance
- Prader-Willi syndrome
  - cause
    - deletion or mutation of normally active paternal allele on 15q
    - remember: Prader = paternal deletion
  - presentation
    - mental retardation
    - hyperphagia → obesity
    - hypogonadism
    - neonatal hypotonia
    - behavior problems
  - affects both male and females
- Angelman's syndrome
  - cause
    - disruption of the maternally expressed and paternally imprinted gene UBE3A, which encodes an E3 ubiquitin ligase
    - typically results from deletion of the normally active maternal allele on chromosome 15q
      - same region of the genome as Prader-Willi syndrome deletion but opposite chromosome (not the same gene)
  - presentation
    - severe cognitive disability
    - frequent seizures
    - ataxia
    - speech impairment
    - hyperactivity
    - inappropriate laughter
      - "happy puppet"
  - affects both male and females