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Originally published as Genetics Published Articles Ahead of Print on December 18, 2006.
Genetics, Vol. 175, 585-593, February 2007, Copyright © 2007
doi:10.1534/genetics.106.067751
Histone H3 Lysine 36 Methylation Antagonizes Silencing in Saccharomyces cerevisiae Independently of the Rpd3S Histone Deacetylase Complex
Rachel Tompa and Hiten D. Madhani1
Department of Biochemistry and Biophysics, University of California, San Francisco, California 94143-2200
1 Corresponding author: Genentech Hall, 600 16th St., Room N372C, San Francisco, CA 94143-2200.
E-mail: hiten{at}biochem.ucsf.edu
In yeast, methylation of histone H3 on lysine 36 (H3-K36) is catalyzed by the NSD1 leukemia oncoprotein homolog Set2. The histone deacetylase complex Rpd3S is recruited to chromatin via binding of the chromodomain protein Eaf3 to methylated H3-K36 to prevent erroneous transcription initiation. Here we identify a distinct function for H3-K36 methylation. We used random mutagenesis of histones H3 and H4 followed by a reporter-based screen to identify residues necessary to prevent the ectopic spread of silencing from the silent mating-type locus HMRa into flanking euchromatin. Mutations in H3-K36 or deletion of SET2 caused ectopic silencing of a heterochromatin-adjacent reporter. Transcriptional profiling revealed that telomere-proximal genes are enriched for those that display decreased expression in a set2
strain. Deletion of SIR4 rescued the expression defect of 26 of 37 telomere-proximal genes with reduced expression in set2 cells, implying that H3-K36 methylation prevents the spread of telomeric silencing. Indeed, Sir3 spreads from heterochromatin into neighboring euchromatin in set2 cells. Furthermore, genetic experiments demonstrated that cells lacking the Rpd3S-specific subunits Eaf3 or Rco1 did not display the anti-silencing phenotype of mutations in SET2 or H3-K36. Thus, antagonism of silencing is independent of the only known effector of this conserved histone modification.
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