Stress controls heterochromatin inheritance through histone H3 ubiquitylation [RNA-Seq]
Heterochromatin, marked by histone H3 lysine 9 methylation, can be inherited through cell divisions, maintaining gene repression that preserves cell identity and enables adaptation to environmental challenges. Studies in S. pombe have shown that heterochromatin propagation depends on the read-write mechanism wherein sufficient density of H3K9me3-modified nucleosomes, stabilized by histone deacetylases (HDACs), concentrate Clr4SUV39H on chromatin to promote further deposition of H3K9 methylation. Whether additional mechanisms control heterochromatin propagation via Clr4SUV39H, a part of the E3 ubiquitin ligase complex ClrC, was unknown. Here we uncover a ubiquitin-dependent heterochromatin-heritability regulatory hub (HRH) that broadly governs heterochromatin propagation, even without HDAC activity. The HRH is tuned by the limiting factor Raf1DDB2, a substrate receptor for ClrC ubiquitin ligase. In addition to linking Clr4SUV39H to other ClrC components on chromatin, Raf1DDB2 acts in a dosage-dependent manner to promote ubiquitination of histone H3 at lysine 14 (H3K14ub), which is critical for heterochromatin self-propagation. Importantly, HRH is intricately linked to environmentally responsive pathways, including nonsense-mediated decay (NMD) and TOR signaling, allowing cells to adapt to changing conditions. By modulating heterochromatin propagation, cells leverage the HRH to gain resistance to antifungal agents and to adapt to high temperature. Thus, heterochromatin self-propagation is actively regulated by the HRH in response to external stimuli, with broad implications for understanding mechanisms governing rapid changes in the epigenetic landscape in physiology and disease. Overall design: RNA-Seq of transcripts in Schizosaccharomyces pombe cells