Chromatin Remodelling
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Direct answer
Nearly two metres of DNA wind onto nucleosomes — 147 base pairs coiled around an octamer of two each of histones H2A, H2B, H3 and H4 — and chromatin remodelling is the machinery that opens and closes genes within that packing. Two enzyme families do the work. ATP-dependent remodellers such as SWI/SNF slide, reposition or eject nucleosomes to expose promoters. Histone-modifying enzymes rewrite the histone code: acetyltransferases (p300/CBP) neutralise lysine charges and open chromatin, deacetylases close it, and methyltransferases and kinases add further marks read by bromodomain and chromodomain proteins. DNA methylation at CpG islands superimposes a durable silencing layer.
What you must remember
- Nucleosome arithmetic: 147 base pairs per nucleosome, H1 seals the linker DNA, the 10-nm "beads-on-a-string" folds into the 30-nm fibre — the numbers examiners quote.
- Acetylation opens: histone acetyltransferases (p300/CBP, PCAF) neutralise the lysine positive charge, loosening DNA grip — "acetylation equals transcription on" is the shorthand worth writing.
- Deacetylation closes: HDACs repress; inhibitors include vorinostat and romidepsin (cutaneous T-cell lymphoma) and — a favourite cross-disciplinary fact — sodium valproate, the antiepileptic.
- SWI/SNF (BAF) complexes: ATPase-driven nucleosome sliders; loss of the SMARCB1 subunit defines malignant rhabdoid tumour of childhood, and BAF mutations appear across many cancers.
- DNA methylation: DNMT1 is the maintenance methylase copying marks to the daughter strand; DNMT3A/3B write new marks; 5-azacytidine and decitabine trap DNMTs and are standard in myelodysplastic syndromes.
- Readers, writers, erasers: the histone code framework — bromodomains read acetyl-lysine, chromodomains read methyl-lysine — and mutations in the reader MECP2 cause Rett syndrome.
- Higher-order phenomena to name-drop: X-chromosome inactivation by XIST RNA and the Barr body, imprinting at the Prader-Willi/Angelman region, and position-effect variegation from heterochromatin spread.
- Transcription-factor access is the end point: remodelling exists so that factors can bind; closed chromatin is the default eukaryotic state.
An epigenetics clinic, walked through
Sit the inhibitors side by side and the therapy follows the biology. In myelodysplastic syndrome, decitabine incorporates into DNA as a cytosine analogue and covalently traps DNMTs as they attempt methylation, demethylating silenced tumour-suppressor promoters — an epigenetic drug for a blood cancer. In relapsed cutaneous T-cell lymphoma, vorinostat blocks HDACs, leaving acetyl groups in place and re-expressing genes like p21 that push lymphoma cells toward cell-cycle arrest. Meanwhile, in neurology, valproate — prescribed for decades before its mechanism was appreciated — inhibits class I HDACs, which is the mechanistic thread behind its teratogenicity and its investigational use in sickle-cell disease (re-inducing fetal haemoglobin). One mechanistic family, three specialties. If a viva asks "why is epigenetic therapy attractive", the answer is reversibility: no mutation needs correcting, only marks need rewriting.
Where students slip
Acetylation-versus-methylation confusion leads the list, and the trap is that histone methylation is context-dependent — H3K4 methylation marks active genes while H3K9 methylation marks silent ones, so "methylation always represses" is wrong at histones even though it is mostly right at DNA. The second slip merges two machines: ATP-dependent remodellers physically move nucleosomes, histone modifiers chemically alter them — different complexes, different consequences, and saying "SWI/SNF acetylates histones" fails the answer. Third, DNMT1 versus DNMT3 swap roles under exam pressure: DNMT1 maintains, DNMT3 writes anew. The imprinting link is the Indian postgraduate's favourite angle — Prader-Willi and Angelman syndromes share one locus and are separated by methylation status and parental origin, a one-line answer that shows the whole concept was absorbed.
Frequently asked questions
What does histone acetyltransferase do to chromatin?
It transfers acetyl groups to lysine residues, neutralising their positive charge, weakening histone-DNA attraction and opening chromatin to transcription factors.
Which chromatin-remodelling complexes hydrolyse ATP to move nucleosomes?
SWI/SNF (BAF) family complexes, whose ATPase subunits slide or eject nucleosomes; SMARCB1 loss causes malignant rhabdoid tumour.
How does 5-azacytidine reactivate silenced genes?
It incorporates into DNA and traps DNA methyltransferases during replication, depleting methylation at CpG islands and re-expressing hypermethylated promoters.
Which gene is mutated in Rett syndrome, and what does it encode?
MECP2, on the X chromosome, encoding the methyl-CpG-binding protein that reads DNA methylation — a reader of the epigenetic code.
What distinguishes DNMT1 from DNMT3 enzymes?
DNMT1 is the maintenance methyltransferase copying existing marks onto newly synthesised strands, while DNMT3A and 3B establish methylation patterns de novo.