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Chromatin remodeling contributes to the gene reprogramming in AACH; however, the intrinsic regulations remain elusive. We performed a transcriptome analysis for AACH in comparison with pressure-overload-induced pathological cardiac hypertrophy in mice and identified myeloid leukemia factor 1 (MLF1) as an aging-sensitive factor whose expression was reduced during aging but could be reversed by anti-aging administrations. In human AC16 cardiomyocytes, silencing MLF1 suppressed H2O2-induced cell senescence while the phenotype was exacerbated by MLF1 overexpression. RNA-seq analysis revealed that MLF1 functioned as a transcription activator, regulating genomic-clustered genes that mainly involved in inflammation and development. ATAC-seq analysis showed a prominent reduction in chromatin accessibility at the promoter regions of senescence effectors, like IL1B and p21, after MLF1 knockdown. Despite a potential interaction of MLF1 with the histone methyltransferase PRC2, its inhibition failed to reverse the impact of MLF1 knockdown. Instead, MLF1-mediated regulation was blunted by inhibiting the acetyltransferase EP300. CUT&amp;Tag analysis showed that MLF1 bound to target promoters and recruited EP300 to promote H3K27ac deposition. Collectively, we identify MLF1 as a pro-aging epigenetic orchestrator that recruits EP300 to facilitate opening of the condensed chromatin encompassing senescence effectors.<\/jats:p>","DOI":"10.1093\/nar\/gkae1176","type":"journal-article","created":{"date-parts":[[2024,12,10]],"date-time":"2024-12-10T23:51:01Z","timestamp":1733874661000},"source":"Crossref","is-referenced-by-count":16,"title":["Downregulation of MLF1 safeguards cardiomyocytes against senescence-associated chromatin opening"],"prefix":"10.1093","volume":"53","author":[{"given":"Jian","family":"Lv","sequence":"first","affiliation":[{"name":"Shenzhen Key Laboratory of Cardiovascular Disease, Fuwai Shenzhen Hospital, Chinese Academy of Medical Sciences , Shenzhen\u00a0 518057 ,","place":["China"]},{"name":"State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing\u00a0 100037 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