Set2 methylation of histone H3 lysine 36 suppresses histone exchange on transcribed genes

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Set2-mediated methylation of histone H3 at Lys 36 (H3K36me) is a co-transcriptional event that is necessary for the activation of the Rpd3S histone deacetylase complex, thereby maintaining the coding region of genes in a hypoacetylated state1,2. In the absence of Set2, H3K36 or Rpd3S acetylated histones accumulate on open reading frames (ORFs), leading to transcription initiation from cryptic promoters within ORFs1,3. Although the co-transcriptional deacetylation pathway is well characterized, the factors responsible for acetylation are as yet unknown. Here we show that, in yeast, co-transcriptional acetylation is achieved in part by histone exchange over ORFs. In addition to its function of targeting and activating the Rpd3S complex, H3K36 methylation suppresses the interaction of H3 with histone chaperones, histone exchange over coding regions and the incorporation of new acetylated histones. Thus, Set2 functions both to suppress the incorporation of acetylated histones and to signal for the deacetylation of these histones in transcribed genes. By suppressing spurious cryptic transcripts from initiating within ORFs, this pathway is essential to maintain the accuracy of transcription by RNA polymerase II.

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Figure 1: Loss of Set2 results in increased histone exchange and an enrichment of H3K56ac over ORFs.
Figure 2: Increased histone exchange correlates with increased acetylation over ORFs in set2 Δ cells.
Figure 3: Loss of Asf1-mediated exchange in set2 Δ cells decreases the enrichment of acetylated histones over ORFs.
Figure 4: Cryptic transcript phenotype caused by histone chaperone-mediated histone exchange in set2 Δ cells.

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Gene Expression Omnibus

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The data discussed in this paper are deposited in NCBI’s Gene Expression Omnibus under GEO accession number GSE28099 (


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We thank F. Winston and O. Rando for providing yeast strains used in this study, members of the Workman laboratory for discussion, and J. Chatfield and G. Dialynas for critical reading of our manuscript. This work was supported by National Institutes of Health grant R01GM04867 to J.L.W. and the Stowers Institute for Medical Research.

Author information

S.V. and J.L.W. designed the study. S.V. performed the experiments and analysed the data. M. Smolle, M. Saint and S.K. helped out with experiments. H.L. and M.M.G. wrote the R scripts used to analyse the data. K.N. provided laboratory space and resources for a part of the study. S.V. and J.L.W. wrote the manuscript.

Correspondence to Jerry L. Workman.

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Venkatesh, S., Smolle, M., Li, H. et al. Set2 methylation of histone H3 lysine 36 suppresses histone exchange on transcribed genes. Nature 489, 452–455 (2012) doi:10.1038/nature11326

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