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Structure paper

TitleMolecular mechanism of co-transcriptional H3K36 methylation by SETD2.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 9565, Year 2025
Publish dateOct 29, 2025
AuthorsJames L Walshe / Moritz Ochmann / Ute Neef / Olexandr Dybkov / Christian Dienemann / Christiane Oberthür / Aiturgan Zheenbekova / Henning Urlaub / Patrick Cramer /
PubMed AbstractH3K36me3 is a hallmark of actively and recently transcribed genes and contributes to cellular memory and identity. The deposition of H3K36me3 occurs co-transcriptionally when the methyltransferase ...H3K36me3 is a hallmark of actively and recently transcribed genes and contributes to cellular memory and identity. The deposition of H3K36me3 occurs co-transcriptionally when the methyltransferase SETD2 associates with RNA polymerase II. Here we present three cryo-EM structures of SETD2 bound to RNA polymerase II elongation complexes at different states of nucleosome passage. Together with functional probing, our results suggest a 3-step mechanism of transcription-coupled H3K36me3 deposition. First, binding to the elongation factor SPT6 tethers the catalytic SET domain in proximity to the upstream DNA. Second, RNA polymerase II nucleosome passage leads to the transfer of a hexasome from downstream to upstream, poised for methylation. Finally, continued transcription leads to upstream nucleosome reassembly, partial dissociation of the histone chaperone FACT and sequential methylation of both H3 tails, completing H3K36me3 deposition of an upstream nucleosome after RNA polymerase II passage.
External linksNat Commun / PubMed:41162378 / PubMed Central
MethodsEM (single particle)
Resolution3.58 - 6.72 Å
Structure data

51643

9gw2

EMDB-51643, PDB-9gw2:
State 2 MAP 1 SETD2 bound to proximal H3 of upstream nucleosome
Method: EM (single particle) / Resolution: 4.84 Å

54247

9rtn

EMDB-54247, PDB-9rtn:
State 2 MAP 2 SPT6 with SETD2
Method: EM (single particle) / Resolution: 3.82 Å

54399

9rzc

EMDB-54399, PDB-9rzc:
State 3 MAP 1 SETD2 bound to distal H3 of upstream nucleosome
Method: EM (single particle) / Resolution: 3.66 Å

54400

9rzd

EMDB-54400, PDB-9rzd:
State 3 MAP 2 SPT6 with SETD2
Method: EM (single particle) / Resolution: 3.69 Å

54425

9s0u

EMDB-54425, PDB-9s0u:
State 3 MAP 3 RNA Pol II activated elongation complex with SETD2 bound to distal upstream H3
Method: EM (single particle) / Resolution: 6.72 Å

54537

9s3g

EMDB-54537, PDB-9s3g:
State 1 MAP3 RNA Pol II activated elongation complex with SETD2 and upstream hexasome
Method: EM (single particle) / Resolution: 6.4 Å

EMDB-54538: State 1 MAP1 RNA Pol II activated elongation complex with SETD2 and upstream hexasome
Method: EM (single particle) / Resolution: 3.89 Å

EMDB-54541: State 1 MAP2 RNA Pol II activated elongation complex with SETD2 and upstream hexasome
Method: EM (single particle) / Resolution: 3.71 Å

EMDB-54542: State 1 MAP4 RNA Pol II activated elongation complex with SETD2 and upstream hexasome
Method: EM (single particle) / Resolution: 3.58 Å

Chemicals

ChemComp-ZN:
Unknown entry

ChemComp-MG:
Unknown entry

Source
  • homo sapiens (human)
  • synthetic construct (others)
  • sus scrofa (pig)
KeywordsTRANSCRIPTION / RNA Pol II Activated elongation complex Co-transcriptional H3K36me3 SETD2

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