Up-Regulation of A Male-Specific H3K4 Demethyl-ase, KDM5D, Is Required for Cardiomyocyte Differentia-tion

Background: Y chromosome human proteome project (Y-HPP) has been implemented with a great mission to investigate the Y chromosome proteins expression and function, not only in sex determination and fertility, but also in organ develop-ment and organ-specific function. Previously, we showed that some Y chromosome genes are differentially expressed dur-ing cardiogenic differentiation of human embryonic stem cells (hESC). Among them, KDM5D along with its X-counterpart, KDM5C, were overexpressed during cardiac mesoderm stage. Materials and Methods: The function of KDM5D in cadio-myocyte differentiation was assessed by knocking down of its expression using siRNA. At 48 hours after siRNA transfection, the siKDM5D transfected cells were analyzed for cell cycle progression. The expression of KDM5D, KDM5C and some of cardiac progenitor specific markers was assessed following KDM5D knockdown. Furthermore, the function of differentiat-ed cardiomyocytes was studied by multielectrode array (MEA) systemResults: Although the expression level of KDM5C remained unchanged, down-regulation of KDM5D resulted in a substan-tial growth of differentiating cell population in S-phase of cell cycle while the expression level of cardiac progenitor specific markers diminished. Furthermore, no spontaneous beating was observed in KDM5D down-regulated cells while the beating was started in control cells on day 7 of cardiac induction.Conclusion: Our findings show that KDM5D in co-operation with its X homologue as dose-sensitive genes are necessary for cardiomyocyte differentiation and provide further evidence on the importance of Y chromosome genes in cardiac development beyond sex determination.

کلیدواژه ها:

KDM5D ، Y-HPP ، Y chromosome ، Cardiac Develop-ment