Coordination of cell cycle progression and mitotic spindle assembly involves histone H3 lysine 4 methylation by set1/COMPASS

Methylation of histone H3 lysine 4 (H3K4) by Set1 complex/COMPASS is a hallmark of eukaryotic chromatin but it remains poorly understood how this posttranslational modification contributes to the regulation of biological processes like the cell cycle. Here, we report a H3K4 methylation dependent pathway in Saccharomyces cerevisiae that governs toxicity towards benomyl, a microtubule destabilizing drug. Benomyl sensitive growth of wild-type cells required mono- and di-methylation of H3K4 and Pho23, a PHD containing subunit of the Rpd3L complex. Δset1 and Δpho23 deletions suppressed defects associated with ipl1-2 aurora kinase mutant, an integral component of the spindle assembly checkpoint during mitosis. Benomyl resistance of Δset1 strains was accompanied by de-regulation of all four tubulin genes and the phenotype was suppressed by tub2-423 and Δtub3 mutations, establishing a genetic link between H3K4 methylation and microtubule function. Most interestingly, sine wave fitting and clustering of transcript abundance time series in synchronised cells revealed a requirement for Set1 for proper cell cycle dependent gene expression and Δset1 cells displayed delayed entry into S phase. Disruption of G1/S regulation in Δmbp1 and Δswi4 transcription factor mutants duplicated both benomyl resistance and suppression of ipl1 2 as was observed with Δset1 . Taken together our results support a role for H3K4 methylation in the coordination of cell cycle progression and proper assembly of the mitotic spindle during mitosis.