Molecular mechanism of co-transcriptional H3K36 methylation by SETD2

James L. Walshe (), Moritz Ochmann, Ute Neef, Olexandr Dybkov, Christian Dienemann, Christiane Oberthür, Aiturgan Zheenbekova, Henning Urlaub and Patrick Cramer ()
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James L. Walshe: Max Planck Institute for Multidisciplinary Sciences
Moritz Ochmann: Max Planck Institute for Multidisciplinary Sciences
Ute Neef: Max Planck Institute for Multidisciplinary Sciences
Olexandr Dybkov: Max Planck Institute for Multidisciplinary Sciences
Christian Dienemann: Max Planck Institute for Multidisciplinary Sciences
Christiane Oberthür: Max Planck Institute for Multidisciplinary Sciences
Aiturgan Zheenbekova: Max Planck Institute for Multidisciplinary Sciences
Henning Urlaub: Max Planck Institute for Multidisciplinary Sciences
Patrick Cramer: Max Planck Institute for Multidisciplinary Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-65439-y

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