| First Author | Lv J | Year | 2025 |
| Journal | Nucleic Acids Res | Volume | 53 |
| Issue | 2 | PubMed ID | 39657728 |
| Mgi Jnum | J:361573 | Mgi Id | MGI:7858320 |
| Doi | 10.1093/nar/gkae1176 | Citation | Lv J, et al. (2025) Downregulation of MLF1 safeguards cardiomyocytes against senescence-associated chromatin opening. Nucleic Acids Res 53(2) |
| abstractText | Aging-associated cardiac hypertrophy (AACH) increases susceptibility to heart failure in the elderly. 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&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. |
