Epigenetic changes (DNA methylation, MicroRNAs) and role in carcinogenesis

1. Concept

Epigenetics = heritable, reversible changes in gene expression without altering the DNA sequence. Main mechanisms: DNA methylation, microRNAs, histone modification. Their reversibility makes them drug targets.

2. DNA methylation

• A methyl group is added (by DNA methyltransferase) to cytosines in CpG islands of promoters → transcriptional silencing.
• Promoter hypermethylation silences tumor suppressor genes:
  • RB → retinoblastoma; BRCA1 → breast/ovarian; CDKN2A/p16, ARF → colon/stomach; MLH1.
• Global hypomethylation → genomic instability + oncogene activation.

3. MicroRNAs (miRNA)

• Small non-coding RNAs that negatively regulate gene expression post-transcriptionally.
• Processing: pre-miRNA exported from nucleus → cut by Dicer → mature miRNA → loaded into RISC → base-pairs with target mRNA → cleavage or translational repression.
• In cancer:
  • Loss of a tumor-suppressor miRNA → target oncogene overexpressed (e.g. miRNA deletion → ↑BCL2 in leukemia/lymphoma).
  • Overexpressed oncomiR (e.g. miR-21) → represses tumor suppressors.

4. Histone modification

• Histone N-terminal tails control chromatin packing; modifications can be oncogenic if dysregulated.
• Acetylation (HAT opens chromatin / HDAC closes it), methylation (lysine, SET-domain proteins), phosphorylation.

💡 High-yield: Epigenetic = heritable, reversible, no sequence change. Promoter hypermethylation silences tumor suppressors (BRCA1, MLH1, p16); global hypomethylation → instability. miRNA: loss of tumor-suppressor miRNA → ↑oncogene; oncomiR (miR-21) → ↓suppressors. Histones: HAT/HDAC acetylation. Reversibility → DNMT/HDAC inhibitors.