biostudies-literatureWang CU.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)NIDDK NIH HHSNIA NIH HHSU.S. Department of Health & Human Services | NIH | National Cancer InstituteNCI NIH HHSU.S. Department of Health & Human Services | National Institutes of Health (NIH)U.S. Department of Health & Human Services | National Institutes of HealthNIH HHSNIGMS NIH HHS5410https://www.ebi.ac.uk/biostudies/studies/S-EPMC11208586biostudies-literatureUnknown15(1)METTL3 is the catalytic subunit of the methyltransferase complex, which mediates m⁶A modification to regulate gene expression. In addition, METTL3 regulates transcription in an enzymatic activity-independent manner by driving changes in high-order chromatin structure. However, how these functions of the methyltransferase complex are coordinated remains unknown. Here we show that the methyltransferase complex coordinates its enzymatic activity-dependent and independent functions to regulate cellular senescence, a state of stable cell growth arrest. Specifically, METTL3-mediated chromatin loops induce Hexokinase 2 expression through the three-dimensional chromatin organization during senescence. Elevated Hexokinase 2 expression subsequently promotes liquid-liquid phase separation,Nature communicationsMETTL3-mediated chromatin contacts promote stress granule phase separation through metabolic reprogramming during senescence.PMC11208586R01 CA160331OT2 OD030544U2C DK119886P30 CA010815R00 AG065500R01CA160331R01 CA276569P30 CA030199P01 AG031862R01CA276569P30 CA016672P01AG031862R35 GM153277R01 GM129069Havas AWang CAdams PDTian BHao XGardini AGoldman AKossenkov AVZhang RZhang QNie HWang LLiao LHill CTanizawa HNoma KILei XQi YBerger SLfalseMETTL3-mediated chromatin contacts promote stress granule phase separation through metabolic reprogramming during senescence.METTL3 is the catalytic subunit of the methyltransferase complex, which mediates m⁶A modification to regulate gene expression. In addition, METTL3 regulates transcription in an enzymatic activity-independent manner by driving changes in high-order chromatin structure. However, how these functions of the methyltransferase complex are coordinated remains unknown. Here we show that the methyltransferase complex coordinates its enzymatic activity-dependent and independent functions to regulate cellular senescence, a state of stable cell growth arrest. Specifically, METTL3-mediated chromatin loops induce Hexokinase 2 expression through the three-dimensional chromatin organization during senescence. Elevated Hexokinase 2 expression subsequently promotes liquid-liquid phase separation,2024-01-01T00:00:00Z2024 Jun2026-06-01T23:38:19.305Z2025-04-04T21:22:28.799ZS-EPMC112085863892636510.1038/s41467-024-49745-5