H3K36 Methylation Regulates Nutrient Stress Response in S. cerevisiae by Enforcing Transcriptional Fidelity

Set2-mediated methylation of H3K36 (H3K36me) regulates a diverse number of activities including DNA repair, mRNA splicing and the suppression of inappropriate or 'cryptic' transcription. Here, we describe an unexpected connection between Set2-mediated H3K36me and the regulation of nutrient stress response. We find cells deleted for SET2 (set2?) are sensitive to inhibitors of Tor1, Tor2 and MAP kinase pathways that regulate the nutrient response pathway. Further genetic and biochemical analyses confirm a role for Set2-mediated H3K36me in nutrient stress response. At the molecular level, set2? cells demonstrate a dysregulated genome-wide transcriptional response to nutrient stress. Remarkably, newly initiated and bi-directional transcription events within the bodies of genes develop in set2? cells during nutrient stress. Importantly, these antisense transcripts extend into the promoters of the genes they arise from, resulting in pervasive transcriptional interference. Our results suggest that Set2-enforced transcriptional fidelity is critical to the proper regulation highly-tuned transcription programs. Overall design: Examination of ribosome-depleted stranded RNA in WT or set2? in S. cerevisiae at 0, 30, 60, and 120 minutes after nutrient stress.

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McDaniel SL, Hepperla AJ, Huang J, Dronamraju R, Adams AT, Kulkarni VG, Davis IJ, Strahl BD