STEPTRACKERBIOCHEMISTRY | MOLECULAR BIOLOGY | HIGH-YIELD REVIEW

Chromatin & Epigenetics

How DNA is packed, and how chemical tags on DNA and histones switch genes on or off without changing the sequence.

FOCUS ON
DNA wraps around a histone octamer (H2A, H2B, H3, H4 ×2) = nucleosome; H1 ties nucleosomes together. Heterochromatin = condensed, silent; euchromatin = open, active. DNA methylation (CpG islands) silences; histone acetylation opens (relaxes) chromatin; histone deacetylation tightens it. Methylation underlies imprinting and X inactivation.
FEATURE
WHAT IT IS
EFFECT ON GENES
CLUE · EXAMPLE
Nucleosome
"beads on a string"
~147 bp of DNA wrapped around 8 histones (2 each of H2A, H2B, H3, H4); histones are rich in lysine and arginine (positive charge binds negative DNA)
Basic unit of packing
H1 is the linker histone — not in the core
Heterochromatin
Condensed chromatin; dark on EM; often methylated and deacetylated
Transcriptionally silent
Barr body (inactive X) · centromeres, telomeres
Euchromatin
Loose, light-staining chromatin
Transcriptionally active
Large nucleoli, open chromatin in active cells
DNA methylation
DNA methyltransferase adds methyl to cytosine in CpG islands of promoters
Represses transcription
Imprinting · X inactivation · tumor suppressor silencing; fragile X (FMR1 hypermethylation)
Histone acetylation
Histone acetyltransferase removes the + charge on lysines → DNA loosens
Activates transcription ("acetylation = active")
HDAC inhibitors (vorinostat) re-activate silenced genes in lymphoma
Histone deacetylation
HDACs restore the + charge → tighter packing
Represses transcription
Huntington protein may increase deacetylation → silencing
Histone methylation
Methyl groups on lysine/arginine of histones
Can activate or repress (site-dependent)
Contrast: DNA methylation almost always represses
Genomic imprinting
Only one parental allele is expressed; the other is silenced by methylation
Loss of the active allele → disease
Prader-Willi (paternal loss) · Angelman (maternal loss) — see 5.04
X inactivation
lyonization
XIST RNA coats one X in each female cell early in development; random, then fixed
Females are mosaics for X genes
Skewed inactivation → manifesting carriers of X-linked disease
Epigenetic drugs
Azacitidine, decitabine (DNA methyltransferase inhibitors) · vorinostat, romidepsin (HDAC inhibitors)
Re-express silenced genes
Myelodysplastic syndrome · cutaneous T-cell lymphoma

Mechanism — opening and closing chromatin

Histone acetylationLysine loses + charge
→
DNA loosensEuchromatin
→
Transcription ON
DNA methylation / deacetylationCpG methyl, + charge back
→
Tight packingHeterochromatin
→
Transcription OFF

The sequence never changes — which is why epigenetic marks are reversible and drug-targetable.

Heterochromatin vs euchromatin

FEATURE
HETEROCHROMATIN
EUCHROMATIN
Packing
Condensed
Open
EM / stain
Dark
Light
Activity
Silent
Active
Typical marks
DNA methylation, deacetylated histones
Acetylated histones
Example
Barr body, centromere
Housekeeping genes

How it's tested

COMMON CONFUSIONDNA methylation silences genes; histone methylation can go either way. Histone acetylation always relaxes chromatin.
THE TRAPA question about "which amino acids make histones bind DNA" wants lysine and arginine (positively charged), not aspartate or glutamate.
YOUR APPROACHAsk: is the mark on DNA or on a histone? Does it add or remove charge? Tight = off, loose = on.

If you see… think…

Dark, condensed chromatin on EM → heterochromatin (silent)
Barr body in a female cell → inactivated, methylated X
Tumor suppressor silenced without a mutation → promoter CpG methylation
Drug that inhibits DNA methyltransferase in MDS → azacitidine / decitabine
HDAC inhibitor for cutaneous T-cell lymphoma → vorinostat
Histones are rich in → lysine and arginine
Linker histone outside the core octamer → H1
Fragile X gene switched off → FMR1 promoter hypermethylation
Female carrier with symptoms of an X-linked disease → skewed X inactivation
Only one parent's copy of a gene expressed → genomic imprinting