Epigenetic mechanisms

DNA Methylation - Silencing the Code

• Mechanism: Covalent addition of a methyl group to cytosine bases within CpG dinucleotides (CpG islands).
• Enzyme: DNA Methyltransferase (DNMT).
• Methyl Donor: S-adenosyl methionine (SAM).
• Function: Gene silencing. Methylated DNA physically obstructs transcription factors and recruits histone deacetylases (HDACs), leading to chromatin condensation (heterochromatin).
• Clinical Relevance:
  • Genomic imprinting (e.g., Prader-Willi, Angelman syndromes).
  • X-chromosome inactivation (Lyonization).
  • Tumor suppressor gene silencing in cancer.

⭐ CpG islands are often located in the promoter regions of genes. Hypermethylation of a tumor suppressor gene's promoter CpG island is a common mechanism for its inactivation in neoplasia.

Histone Modification - Spooling the Rules

• Core Concept: Positively charged lysine residues in histones bind to negatively charged DNA phosphate groups, regulating DNA accessibility.

• Histone Acetylation:

  • Mechanism: Histone Acetyltransferases (HATs) add acetyl groups ($CH_3CO$) to lysine, neutralizing its positive charge.
  • Result: ↓ DNA-histone affinity → relaxed chromatin (euchromatin) → ↑ transcription.
  • 📌 Histone Acetylation Turns genes Active.

• Histone Deacetylation:

  • Mechanism: Histone Deacetylases (HDACs) remove acetyl groups.
  • Result: ↑ DNA-histone affinity → condensed chromatin (heterochromatin) → ↓ transcription.

• Histone Methylation:

  • Mechanism: Histone Methyltransferases (HMTs) add methyl groups ($CH_3$) to lysine or arginine.
  • Result: Variable; typically causes reversible gene silencing (heterochromatin), but can also activate transcription depending on the location.
  • 📌 Histone Methylation Makes DNA Mute (usually).

⭐ Huntington Disease: Involves abnormal huntingtin protein interaction with HATs and HDACs, leading to histone hypoacetylation and transcriptional repression of neuroprotective genes.

Genomic Imprinting - Parental Grudges

• Process where gene expression is determined by parental origin. Only one allele (maternal or paternal) is expressed, while the other is silenced via methylation.
• Mechanism: Methylation of CpG islands in the promoter region silences the gene. This occurs during gametogenesis.

• Clinical Syndromes (Chromosome 15q11-q13):
  • Prader-Willi Syndrome: Paternal allele is deleted or mutated.
    • Maternal allele is normally imprinted (silenced).
    • Features: Hyperphagia, obesity, intellectual disability, hypogonadism.
    • 📌 Prader-Willi: Paternal deletion.
  • Angelman Syndrome: Maternal allele is deleted or mutated.
    • Paternal allele is normally imprinted (silenced).
    • Features: "Happy puppet," seizures, ataxia, severe intellectual disability.
    • 📌 Angelman: Maternal deletion.

⭐ Uniparental disomy (UPD), where an individual inherits two copies of a chromosome from one parent and none from the other, is another cause for both Prader-Willi (maternal UPD) and Angelman (paternal UPD) syndromes.

High‑Yield Points - ⚡ Biggest Takeaways

• DNA methylation at CpG islands typically represses transcription.
• Histone acetylation creates euchromatin (relaxed), making DNA accessible and ↑ transcription.
• Histone deacetylation forms heterochromatin (condensed), silencing genes by ↓ transcription.
• Histone methylation can either activate or repress transcription depending on the methylation site.
• Genomic imprinting silences genes based on parental origin, as seen in Prader-Willi and Angelman syndromes.
• Fragile X syndrome is caused by hypermethylation of a CGG repeat expansion, silencing the FMR1 gene.