Department of Biochemistry and Biophysics, University of California, 600 16th Street, MC 2200, San Francisco, CA 94158, USA-
Abstract: In Saccharomyces cerevisiae, several nonessential mechanisms including histone variant H2A-Z deposition and transcription-associated histone H3 methylation antagonize the local spread of Sir-dependent silent chromatin into adjacent euchromatic regions- However, it is unclear how and where these factors cooperate- To probe this question, we performed systematic genetic array screens for gene deletions that cause a synthetic growth defect in an htz1Delta mutant but not in an htz1Delta sir3Delta double mutant- Of the four genes identified, three, SET1, SWD1, and SWD3, encode components of the Set1 complex, which catalyzes the methylation of histone H3 on lysine 4 -H3-K4-, a highly conserved modification that occurs in the coding sequences of transcribed genes- Using microarray-based transcriptional profiling, we find that H2A-Z and Set1 cooperate to prevent Sir-dependent repression of a large number of genes located across the genome, rather than the local effects reported previously for the individual mechanisms- This global, redundant function appears to be direct- using a DamID chromatin profiling method, we demonstrate ectopic association of Sir3 and Sir4 in htz1Delta set1Delta mutants at loci distant from silent chromatin domains- Antisilencing mechanisms may therefore cooperate to play a considerably broader role in regulating genome-wide transcription than previously thought-