EM

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.