The effects of β-catenin on cardiomyogenesis via Islet-1 and MLIP ubiquitination

Mesenchymal stem cells (MSCs) can treat myocardial injury–related diseases by differentiating into cardiomyocytes. Islet-1 plays an essential role in cardiac maturation. We have discovered that Islet-1 plays a crucial role in the histone acetylation regulation in this process. In addition, to increase GATA4/Nkx2.5 expression, Islet-1 may bind to Gcn5 and then guide Gcn5 to the GATA4/Nkx2.5 promoters, thereby facilitating the differentiation of MSCs into cardiomyocytes. Islet-1 is an important factor in the maturation of the heart. We have previously found that the pivotal factor in histone acetylation regulation in this process is Islet-1. Furthermore, Islet-1 and Gcn5 may boost GATA4/Nkx2.5 expression, which in turn promotes cardiomyocyte differentiation from MSCs. But the molecular mechanism of Islet-1 binding to GCN5 has not been elucidated. In this study, we found that the competitive binding relationship between Islet-1 and MLIP and GCN5 affected myocardial differentiation. The key enzymes of ubiquitination modification of MLIP and Islet-1 are UBE3C and WWP1, respectively. When short hairpin RNA (shRNA) was used to inhibit β-catenin expression, we found that the expression of UBE3C was upregulated, modifying MLIP ubiquitination and reducing its expression, and it upregulated Islet-1 by inhibiting the expression of WWP1. By using the chromatin immunoprecipitation (ChIP) and luciferase reporter system, we found that when MLIP binds to Islet-1, it significantly inhibits the transcriptional activity of Islet-1. In summary, our results show that decreasing β-catenin regulates the ubiquitination of Islet-1 and MLIP, affecting their expression, reducing the amount of Islet-1 binding to MLIP, and increasing the amount of binding to GCN5 in the nucleus. Therefore, the transcriptional activity of Islet-1 is significantly activated, inducing C3H10T1/2 cells to differentiate into myocytes. Further knowledge of biochemical pathways, including molecular signaling pathways, can provide more insights into the myocardial differentiation mechanism of MSCs.