Beclin1 Deficiency Unlocks Cardiac Lineage Commitment through Convergent Wnt and BMP Signaling Activation

Beclin1 plays significant roles in cardiac organogenesis. Beclin1 can regulate the fate conversion of fibroblasts into cardiomyocytes. However, the function and mechanism of Beclin1 in regulating early cardiac lineage commitment and differentiation remain unclear. To explore its potential role in cardiac lineage development, we utilized model of cardiomyocyte differentiation from mouse embryonic stem cells (mESCs) to simulate early cardiogenesis and investigated the function of Beclin1. We show that the knockdown of Beclin1 facilitates cardiomyocyte differentiation. Through bulk RNA-sequencing analysis, we found that knocking down Beclin1 activated the Wnt signaling pathway at the embryoid body stage but inhibited its activity at the cardiomyocyte stage. Moreover, the Bone morphogenetic protein (Bmp) signaling pathway was continuously activated throughout cardiomyocyte differentiation process. Our findings demonstrate a novel function of Beclin1 during cardiac differentiation. The activation of Wnt-mediated Bmp signaling pathway represents a major mechanism by which the deficiency of Beclin1 promotes mESCs differentiation into cardiomyocytes. Overall design: To determine the molecular basis by which knockdown Beclin1 enhances cardiomyocyte differentiation, we conducted bulk RNA-sequencing (RNA-seq) with shNT- and shBcelin1-treated mESCs (d0) and their differentiated cells towards cardiac lineage on day 4 and day 10.