Epigenetics and Inheritance

DNA Methylation and Epigenetics

• In eukaryotes, up to 10% of cytosines (C's) are methylated, primarily on CpG islands (1-2 kb in length) near promoters.
  • DNA methyltransferases add methyl groups to DNA de novo and then to all newly synthesized DNA.
  • Epigenetics involves inherited changes to methylation patterns that affect gene expression.

Examples of Epigenetics

• Dosage compensation in mammals (X inactivation).
• Imprinting.

Dosage Compensation in Mammals (X Inactivation)

• Occurs via X inactivation, resulting in a Barr body.

Process:

• Initiation: Occurs during embryonic development. The number of X-inactivation centers (Xics) is counted, and one X chromosome remains active while the other is targeted for inactivation.
• Spreading: Begins at the Xic and progresses towards both ends until the entire chromosome is inactivated. The Xist gene encodes an RNA that coats the X chromosome and recruits proteins to promote compaction into a Barr body.
• Maintenance: Occurs from embryonic development through adult life. The inactivated X chromosome is maintained as such during subsequent cell divisions.

Escape from Inactivation:

• About 20-30% of human genes escape inactivation, including:
  • Genes in PAR.
  • XIST.
  • Other genes.
• This phenomenon is also referred to as "X inactivation-ish."

Example: Mouse Fur Color

• Early embryo: all X chromosomes are active.
  • Random X chromosome inactivation occurs, forming Barr bodies.
  • Further development leads to a mouse with patches of black and white fur.

Genomic Imprinting

• Only one allele is expressed in somatic cells of heterozygous offspring, an allele that is silent in the offspring.

Process

• Establishment of the Imprint: Occurs during gametogenesis in the Igf2 gene, with the Igf2 allele from the male and the Igf2 allele from the female.
  • This imprinting results in only the paternal allele being expressed.
• Maintenance of the Imprint: After fertilization, the imprint pattern is maintained throughout development.
  • For example, the maternal Igf2- allele will not be expressed in somatic cells.
• Erasure and Reestablishment: During gametogenesis, the imprint is erased.
  • The female mouse produces eggs in which the gene is silenced.
  • The male produces sperm in which the gene can be transcribed into mRNA.

Imprinting Mechanism:

• In male cells:
  • Maintenance methylation occurs in all somatic cells.
• In female cells:
  • Erasure (demethylation) occurs in early oocytes.
  • De novo methylation occurs during the formation of sperm.

Example

• Deletion of the same region of chromosome 15 results in different disorders depending on whether inherited maternally or paternally.

Further Considerations

• Nutrigenomics: Influence of diet on the genome.
• Nutrigenetics: Gene variants that affect response to diet.
• Transgenerational Inheritance: Example: fear of acetophenone (= smell of cherry blossoms) in mice (2013).
• Paternal hypercholesterolemia elicits sex-specific exacerbation of atherosclerosis in offspring.
• Epigenetic signatures of intergenerational exposure to violence in three generations of Syrian refugees.