Histone trimethylation by Set1 is coordinated by the RRM, autoinhibitory, and catalytic domains

EMBO J. 2005 Mar 23;24(6):1222-31. doi: 10.1038/sj.emboj.7600607. Epub 2005 Mar 3.


Trimethylation of lysine 4 of histone H3 occurs at the 5' end of active genes and is catalyzed by Set1 in Saccharomyces cerevisiae. Trimethylation requires histone H2B ubiquitylation and the PAF1 complex, which are linked to transcription elongation, but how they activate Set1 is not known. Set1 also bears several conserved domains with uncharacterized contributions to activity. Here, we isolated dominant hyperactive SET1(D) alleles, which revealed a complex interplay among Set1 regulatory domains. Remarkably, the RNA-recognition motif (RRM) of Set1 is required for H3K4 trimethylation, but not dimethylation. Also, a central autoinhibitory domain was identified that opposes RRM function by inhibiting trimethylation. Furthermore, a G990E replacement in the catalytic domain conferred Set1 hyperactivity and restored trimethylation to a Set1 derivative bearing mutations in the RRM domain. Surprisingly, certain SET1(D) alleles also partially restored trimethylation to strains lacking histone H2B ubiquitylation or Paf1. Taken together, our data suggest that the catalytic domain of Set1 integrates opposing inputs from the RRM and autoinhibitory domains to link properly H3K4 methylation to the transcript elongation process.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alleles
  • Amino Acid Motifs
  • Amino Acid Substitution
  • Catalytic Domain / genetics
  • Catalytic Domain / physiology
  • DNA-Binding Proteins / chemistry*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology*
  • Genes, Dominant
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / physiology*
  • Histones / metabolism*
  • Methylation
  • Mutation / genetics
  • Nuclear Proteins
  • Saccharomyces cerevisiae / enzymology*
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / chemistry*
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / physiology*
  • Transcription Factors / chemistry*
  • Transcription Factors / genetics
  • Transcription Factors / physiology*
  • Transcription, Genetic
  • Transcriptional Elongation Factors / physiology


  • DNA-Binding Proteins
  • Histones
  • Nuclear Proteins
  • PAF1 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Transcription Factors
  • Transcriptional Elongation Factors
  • Histone-Lysine N-Methyltransferase
  • SET1 protein, S cerevisiae