Project description:The cooperation among the core regulatory circuitry transcription factors and MYCN on DNA binding [HAND2-MYCN-CRC-knockdown_ChIPseq]
Project description:The knockdown of HAND2 in IMR32 cells results in a decrease of chromation accessibility at the HAND2 and MYCN common binding sites.
Project description:The overexpression of HAND2 in IMR32 cells results in a increase of chromation accessibility at the HAND2 and MYCN common binding sites.
Project description:Heart failure with reduced ejection fraction (HFrEF) remains a major therapeutic challenge. Bcl2-associated transcription factor 1 (Bclaf1) is implicated in RNA splicing and cardiac disease, but its role in HFrEF pathogenesis is unknown. Here, we demonstrate that Bclaf1 expression is elevated in human HFrEF myocardium and in murine pressure-overload models. Cardiac-specific Bclaf1 overexpression drives pathological hypertrophy and systolic dysfunction, whereas its genetic knockout or AAV9-mediated knockdown attenuates these phenotypes. Mechanistically, Bclaf1 interacts with the splicing factor Srsf2 to bind and enhance the splicing efficiency of Hand2 pre-mRNA, leading to increased mature Hand2 levels and maladaptive remodeling. Inhibition of either Bclaf1 or Hand2 rescues cardiac function and structure in experimental HFrEF. Our work defines a novel Bclaf1/Srsf2/Hand2 splicing axis as a critical driver of HFrEF and reveals a promising therapeutic target for heart failure.
