A Histone Code Functionally Linked to Replicative Senescence

Cell states and biological processes are defined by their epigenetic profiles, distinctive composites of DNA- and histone-based chromatin components. However, the specific histone posttranslational modifications that distinguish cellular senescence and the impact of their distribution on transcription, especially with regard to gene length, have not been fully elucidated. Here, we show that promoter loss of symmetric dimethylated H4R3 (H4R3me^(2s)) and spreading of trimethylated H3K79 (H3K79me³) across gene bodies are functional features of replicative senescence associated with gene upregulation. We report that highly upregulated genes in replicative senescence exhibit enrichment of H3K79me³ and, in contrast to the characteristic trend of aging cells and tissues, are substantially longer than those that are significantly downregulated. Furthermore, by assessing all expressed genes, we demonstrate that gene body accumulation of H3K79me³ during the transition to replicative senescence constitutes a broader phenomenon that is positively correlated with gene length and expression level genome-wide. Consistently, pharmacological inhibition of H3K79me³ deposition attenuates gene upregulation in replicative senescence. We also document a striking increase in the levels of H3K79me³ as well as a robust H4R3me^(2s) to asymmetric dimethylated H4R3 (H4R3me^(2as)) epigenetic switch that manifest globally in late-passage cells, suggesting that these histone modifications might represent novel molecular biomarkers of replicative senescence. Finally, we implicate the associated epigenetic regulators, including DOT1L, PRMT1, PRMT5, and JMJD6, as modifiers of cellular lifespan, potentially disclosing unappreciated therapeutic targets for interventions in normal and pathological aging. Collectively, our findings provide novel insights into the histone code that mediates altered transcriptional regulation in replicative senescence.