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.