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Epigenetics refers to heritable changes in gene expression that do not involve changes in the DNA sequence. The two dominant molecular mechanisms are DNA methylation and histone modifications, which together establish chromatin states that are transmissible through cell division. Epigenetic dysregulation underlies imprinting disorders, X-inactivation, and a subset of cancers and developmental syndromes.
- Addition of a methyl group to the 5-carbon of cytosine, producing 5-methylcytosine (5mC).
- Occurs mostly at CpG dinucleotides. Roughly 70% of CpGs in the human genome are methylated.
- CpG islands (dense CpG clusters, usually in promoters) are typically unmethylated; their methylation silences gene expression.
- Catalyzed by DNA methyltransferases: DNMT1 (maintenance, copies methylation after replication); DNMT3A/3B (de novo, establish new methylation during development).
- Reversed by active (TET enzymes) and passive (failure of maintenance) demethylation.
- Histones H2A, H2B, H3, H4 package DNA into nucleosomes. N-terminal tails extend outward and accept covalent modifications.
- Acetylation (by HATs): neutralizes lysine charge, loosens chromatin, activates transcription. Example: H3K27ac marks active enhancers.
- Deacetylation (by HDACs): compacts chromatin, represses transcription.
- Methylation: activates or represses depending on residue. H3K4me3 (active promoters) vs H3K9me3 and H3K27me3 (repressed).
- Phosphorylation, ubiquitination, SUMOylation: additional marks regulating transcription, repair, and condensation.
- Euchromatin: loosely packed, transcriptionally active.
- Heterochromatin: densely packed, repressed. Constitutive (centromeres, telomeres) or facultative (the inactive X).
- A parent-of-origin specific epigenetic mark, typically DNA methylation at an imprinting control region (ICR), silences one allele.
- About 100–150 imprinted genes are currently known, clustered mostly on chromosomes 7, 11, 14, 15, and 20.
- Disruption causes imprinting disorders: Prader-Willi/Angelman (15q11–q13), Beckwith-Wiedemann/Silver-Russell (11p15), Temple/Kagami-Ogata (14q32), transient neonatal diabetes (6q24).
- One X chromosome is epigenetically silenced in XX somatic cells, equalizing X-linked gene expression between sexes.
- Mediated by XIST, a lncRNA that coats the inactive X in cis.
- Usually random; skewed inactivation can mask or unmask X-linked phenotypes in carriers (e.g., hemophilia A expression in female carriers with unfavorable skewing).
- Some genes escape inactivation (about 15% of X-linked genes), explaining sex differences in disease expression.
- Imprinting disorders: listed above.
- Chromatin-opathies / Mendelian disorders of the epigenetic machinery: Rett (MECP2), Rubinstein-Taybi (CREBBP/EP300), Coffin-Siris (SWI/SNF complex: ARID1B, SMARCA4), Kabuki (KMT2D, KDM6A), Wiedemann-Steiner (KMT2A).
- Fragile X syndrome: CGG expansion at FMR1 triggers hypermethylation of the promoter, silencing the gene: a canonical example of epigenetic silencing driven by a DNA sequence change.
- Cancer: global hypomethylation + focal hypermethylation of tumor-suppressor promoters (e.g., MLH1 in sporadic colon cancer).
- DNMT1 = maintenance; DNMT3A/B = de novo. These are commonly confused.
- H3K27me3 silences; H3K27ac activates. Same residue, opposite meanings.
- Fragile X is genetic at its root (CGG expansion) but epigenetic in mechanism (methylation silences FMR1). Testing requires Southern blot or methylation-specific PCR to capture both.
- The inactive X forms the Barr body seen in buccal smears.