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Histone H3 K36 methylation is mediated by a trans-histone methylation pathway involving an interaction between Set2 and histone H4.

Set2-mediated H3 K36 methylation is an important histone modification on chromatin during transcription elongation. Although Set2 associates with the phosphorylated C-terminal domain (CTD) of RNA polymerase II (RNAPII), the mechanism of Set2 binding to chromatin and subsequent exertion of its methyltransferase activity is relatively uncharacterized. We identified a critical lysine residue in histone H4 that is needed for interaction with Set2 and proper H3 K36 di- and trimethylation. We also determined that the N terminus of Set2 contains a histone H4 interaction motif that allows Set2 to bind histone H4 and nucleosomes. A Set2 mutant lacking the histone H4 interaction motif is able to bind to the phosphorylated CTD of RNAPII and associate with gene-specific loci but is defective for H3 K36 di- and trimethylation. In addition, this Set2 mutant shows increased H4 acetylation and resistance to 6-Azauracil. Overall, our study defines a new interaction between Set2 and histone H4 that mediates trans-histone regulation of H3 K36 methylation, which is needed for the preventative maintenance and integrity of the genome.

Pubmed ID: 18923077


  • Du HN
  • Fingerman IM
  • Briggs SD


Genes & development

Publication Data

October 15, 2008

Associated Grants

  • Agency: NIGMS NIH HHS, Id: GM74183
  • Agency: NIGMS NIH HHS, Id: R01 GM074183
  • Agency: NIGMS NIH HHS, Id: R01 GM074183-01A1
  • Agency: NIGMS NIH HHS, Id: R01 GM074183-02
  • Agency: NIGMS NIH HHS, Id: R01 GM074183-03
  • Agency: NIGMS NIH HHS, Id: R01 GM074183-04

Mesh Terms

  • Antimetabolites
  • Blotting, Western
  • Chromatin
  • Chromatin Immunoprecipitation
  • Gene Expression Regulation, Fungal
  • Histones
  • Immunoblotting
  • Immunoprecipitation
  • Lysine
  • Methylation
  • Methyltransferases
  • Mutation
  • Nucleosomes
  • Phosphorylation
  • Protein Kinases
  • Protein Processing, Post-Translational
  • RNA Polymerase II
  • Saccharomyces cerevisiae Proteins
  • Transcription, Genetic
  • Uracil