Gene Expression Regulation: Epigenetics and Chromatin Remodeling
Concept Name
Epigenetics
Genetic Loci
DNMT3A (2p23.3) encodes DNA methyltransferase 3A – mutations in acute myeloid leukemia (AML). HDAC1 (1p35.2‑p35.1) encodes histone deacetylase 1. EZH2 (7q36.1) is a histone methyltransferase (H3K27me3) – mutations in lymphoma.
Intracellular Cascade
DNA methylation (CpG islands) represses transcription. Histone modifications: acetylation (HAT) activates, deacetylation (HDAC) represses. H3K4me3 is an activation mark; H3K27me3 is a repression mark. Chromatin remodeling complexes (SWI/SNF) slide nucleosomes using ATP.
Required Cofactors
S‑adenosylmethionine (SAM) is the methyl donor for DNA and histone methyltransferases. Acetyl‑CoA is the acetyl donor for histone acetyltransferases. Fe²⁺ and α‑ketoglutarate are required for TET dioxygenase (DNA demethylation) and JmjC histone demethylases.
Histology Stains
Immunohistochemistry for 5‑methylcytosine (5‑mC) and 5‑hydroxymethylcytosine (5‑hmC) marks DNA methylation status. H3K27me3 and H3K27ac antibodies mark repressed and active chromatin, respectively.
EM Findings
Heterochromatin appears as electron‑dense clumps at the nuclear periphery. Euchromatin is less dense and centrally located. The Barr body (inactive X chromosome) is visible at the nuclear envelope.
Knockout Phenotype
Knockout of DNMT1 in mice causes embryonic lethality at E9.5 with loss of DNA methylation and imprinting defects. Conditional deletion of EZH2 in B cells blocks germinal center formation.
Specific Toxins
5‑Azacytidine (Vidaza) and decitabine are DNMT inhibitors used in MDS. Vorinostat (SAHA) inhibits HDACs. Valproic acid also has HDAC inhibitor activity.