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TitleStructural mechanism of H3K27 demethylation and crosstalk with heterochromatin markers.
Journal, issue, pagesMol Cell, Vol. 85, Issue 15, Page 2869-22884.e6, Year 2025
Publish dateAug 7, 2025
AuthorsChien-Chu Lin / Yani Zhao / Caroline A Foley / Aspen T Hawkins / Lindsey I James / Stephen V Frye / Robert K McGinty /
PubMed AbstractHistone H3 lysine 27 trimethylation (H3K27me3) is a repressive histone modification that is a hallmark of facultative heterochromatin. H3K27me3 is installed by the polycomb repressive complex 2 (PRC2) ...Histone H3 lysine 27 trimethylation (H3K27me3) is a repressive histone modification that is a hallmark of facultative heterochromatin. H3K27me3 is installed by the polycomb repressive complex 2 (PRC2) and removed by KDM6 family Jumonji C (JmjC) domain demethylases. Structural studies have elucidated how PRC2 functions on nucleosomes and its regulation by local histone modification signatures. However, the molecular mechanisms governing H3K27 demethylation to reactivate silenced chromatin remain poorly understood. Here, we report the cryoelectron microscopy (cryo-EM) structure of mouse KDM6B bound to the nucleosome. Our structure shows how KDM6B engages wrapped nucleosomal DNA together with both extranucleosomal DNA linkers to position its catalytic JmjC domain for H3K27 demethylation. KDM6B induces an overlapped linker DNA conformation consistent with function in a compact chromatin environment. We further show that linker histones and H2AK119ub1, both enriched in heterochromatin, antagonize KDM6B function, suggesting that linker histone eviction and H2A deubiquitylation precede H3K27 demethylation during heterochromatin activation.
External linksMol Cell / PubMed:40683254 / PubMed Central
MethodsEM (single particle)
Resolution3.16 - 4.46 Å
Structure data

EMDB-49676, PDB-9nqu:
KDM6B-nucleosome structure stabilized by H3K27C-UNC8015 covalent conjugate
Method: EM (single particle) / Resolution: 3.16 Å

EMDB-71691: Consensus map of mouse KDM6B in complex with nucleosome
Method: EM (single particle) / Resolution: 3.16 Å

EMDB-71692: Focused map of NCP+trans-linker DNA
Method: EM (single particle) / Resolution: 3.2 Å

EMDB-71693: Focused map of mouse KDM6B+cis-linker DNA
Method: EM (single particle) / Resolution: 4.46 Å

Chemicals

ChemComp-FE:
Unknown entry

ChemComp-ZN:
Unknown entry

ChemComp-OH0:
N-heptanoyl-N-hydroxy-beta-alanine

Source
  • homo sapiens (human)
  • synthetic construct (others)
  • mus musculus (house mouse)
KeywordsGENE REGULATION/DNA / histone H3K27 demethylation / GENE REGULATION / histone / chromatin / epigenetics / GENE REGULATION-DNA complex

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