YTHDF1-mediated m6A RNA regulation controls cardiomyocyte remodeling through KLF11-HIF1α (ChIP-seq)

ABSTRACT: Cardiovascular disease remains the leading cause of mortality globally. While cardiac hypertrophy initially arises as a compensatory adaptation of cardiomyocytes to stress, physiological and pathological cardiac hypertrophy exhibit distinct underlying mechanisms and prognoses. However, the precise mechanisms by which cardiomyocytes differentially respond to various stimuli, resulting in distinct forms of hypertrophy thereby ultimately determining divergent cell fates, remain unclear. Here, we demonstrate that metabolic flexibility governs cardiomyocyte fate during cardiac hypertrophy and identified that this metabolic governance is mediated through YTHDF1-dependent RNA epigenetic regulation. In vivo, cardiomyocyte-specific YTHDF1 deficiency leads to maladaptive cardiac remodeling in response to swimming exercise and additionally exacerbates pathological cardiac remodeling under pressure overload stimulation. In vitro, YTHDF1 functions as a switch to regulate the type of cardiomyocyte hypertrophy in a RNA m6A-dependent manner. The YTHDF1/KLF11/HIF1α axis controls cardiomyocyte fate during hypertrophy via balancing metabolic flexibility to meet energy demands. Cardiac-specific overexpression of YTHDF1 alleviates pathological cardiac remodeling. Our findings reveal a previously unrecognized regulatory pathway wherein YTHDF1 serves as a sensor responding to diverse stresses and controling cardiomyocyte fate during hypertrophy via the YTHDF1/KLF11/Hif1α axis. These results highlight a novel therapeutic approach that may inform the development of exercise intervention strategies, suggesting that enhancing oxidative metabolism may serve as a potential treatment option for cardiac diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE300276 | GEO | 2026/08/15

REPOSITORIES: GEO