Despite evidence for sex-specific cardiovascular physiology and pathophysiology, the biological basis for this dimorphism remains to be explored. Apart from hormonal factors, gender-related characteristics may reside in the function of sex chromosomes during cardiac development. In this study, we investigated the differential expression of the male-specific region of the Y chromosome (MSY) genes and their X counterparts during cardiac differentiation of human embryonic stem cells (hESC). We observed alterations in mRNA and protein levels of TBL1Y, PCDH11Y, ZFY, KDM5D, USP9Y, RPS4Y1, DDX3Y, PRY, XKRY, BCORP1, RBMY, HSFY, and UTY, which accompanied changes in intracellular localization. Of them, the abundance of a Y chromosome missing protein, TBL1Y, showed a significant increase during differentiation while the expression level of its X counterpart decreased. Consistently, reducing TBL1Y cellular level using siRNA approach influenced cardiac differentiation by reducing its efficacy as well as increasing the probability of impaired contractions. TBL1Y knockdown may have negatively impacted cardiogenesis by CtBP stabilization. Furthermore, we presented compelling experimental evidence to distinguish TBL1Y from TBL1X, its highly similar X chromosome homologue, and proposed reclassification of TBL1Y as “found missing protein” (PE1). Our results demonstrated that MSY proteins may play an important role in cardiac development.

中文翻译：

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Y染色体缺失蛋白TBL1Y可能在心脏分化中起重要作用

尽管有针对性别的心血管生理学和病理生理学的证据，但这种二态性的生物学基础仍有待探索。除荷尔蒙因素外，在心脏发育过程中，与性别相关的特征可能还存在于性染色体的功能中。在这项研究中，我们调查了人类胚胎干细胞（hESC）心脏分化过程中Y染色体（MSY）基因的男性特定区域及其X对应基因的差异表达。我们观察到TBL1Y，PCDH11Y，ZFY，KDM5D，USP9Y，RPS4Y1，DDX3Y，PRY，XKRY，mRNA和蛋白水平的变化。BCORP1，RBMY，HSFY和UTY，伴随细胞内定位的变化。其中，Y染色体缺失蛋白TBL1Y的丰度在分化过程中显示出显着增加，而其X对应物的表达水平则下降。一致地，使用siRNA方法降低TBL1Y细胞水平会降低其功效并增加收缩受损的可能性，从而影响心脏分化。TBL1Y敲低可能会对CtBP稳定产生不利的影响。此外，我们提供了令人信服的实验证据来将TBL1Y与TBL1X（其高度相似的X染色体同源物）区分开，并提议将TBL1Y重新分类为“发现的缺失蛋白”（PE1）。我们的结果表明，MSY蛋白可能在心脏发育中起重要作用。