Phase separation of MRG15 delays cellular senescence.

Phase separation, a biophysical process that segregates subcellular environments into condensates, has been recognized for its role in transcriptional regulation. However, the extent of its influence on cellular senescence processes remains to be fully elucidated. We established that MRG15 depletion leads to cellular senescence in human mesenchymal stem cells (hMSCs). MRG15 can form phase-separated liquid condensates via its intrinsically disordered region (IDR). IDR deletion and replacement assays revealed that MRG15 condensation is crucial to hMSC senescence. According to the epigenomic and transcriptomic analysis, MRG15 depletion impacts pathways integral to the cell cycle and the senescence process, as evidenced by the diminished binding and the modified expression of key genes, including p53, CDKN1A, LMNB1, CCNB1, NPM1, MYC, and HMGB2. Our findings establish a link between phase separation and senescence regulation and present a promising new therapeutic target for the alleviation of age-related diseases and the potential extension of lifespan.