GeneticsTier 1Medical Sciences concept

Epigenetic regulation - DNA methylation (cytosine, CpG islands) and histone modification

Core concept

Epigenetic regulation alters gene expression without changing the underlying DNA sequence -- heritable through cell division (and sometimes across generations) but reversible
DNA methylation: addition of a methyl group to cytosine, specifically at CpG dinucleotides -- CpG islands (CpG-dense regions, often near gene promoters) that become heavily methylated cause transcriptional silencing of that gene
Histone modification: acetylation, methylation, phosphorylation of histone tails alter chromatin compaction -- acetylation loosens chromatin (active transcription); deacetylation (histone deacetylase, HDAC) tightens chromatin (silencing)

Promoter CpG island hypermethylation is a recognised mechanism of tumour suppressor gene silencing in cancer -- functionally equivalent to a mutation/deletion inactivating the gene, but achieved epigenetically (reversible, no sequence change) -- an alternative "hit" alongside Knudson's two-hit mutational model
Genomic imprinting: certain genes are expressed from only one parental allele based on methylation marks set during gametogenesis -- the other allele is epigenetically silenced regardless of its sequence
Prader-Willi and Angelman syndromes are the classic imprinting exam pair: deletion of the same 15q11-13 region causes Prader-Willi if the paternal copy is affected (maternal copy normally silenced there) and Angelman if the maternal copy is affected (paternal copy normally silenced) -- same chromosomal region, opposite phenotype depending on parent of origin

Trap: assuming a "normal" gene sequence excludes disease -- hypermethylation-silenced tumour suppressors or imprinting-disrupted genes cause disease without any change to the coding sequence itself, and require methylation-specific testing to detect
HDAC inhibitors and DNA methyltransferase inhibitors (e.g. azacitidine, decitabine) are used therapeutically (e.g. in myelodysplastic syndrome, some lymphomas) specifically to reverse abnormal silencing and re-express suppressed genes
Imprinting disorders require methylation-specific PCR or similar parent-of-origin testing, not standard sequencing, because the DNA sequence itself is normal in most cases (uniparental disomy or an imprinting-centre defect, not a coding mutation)

Promoter hypermethylation silencing is an epigenetic alternative to Knudson's "second hit" -- links directly to that note
Genomic imprinting explains why uniparental disomy (both copies of a chromosome from one parent) can cause disease even with a completely normal gene sequence
X-inactivation (Barr body formation, another epigenetic silencing mechanism) uses related chromatin-modification principles to silence one X chromosome per cell in females

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