Sex-dependent gene regulatory networks of the heart rhythm.

Expression level, control, and intercoordination of 66 selected heart rhythm determinant (HRD) genes were compared in atria and ventricles of four male and four female adult mice. We found that genes encoding various adrenergic receptors, ankyrins, ion channels and transporters, connexins, cadherins, plakophilins, and other components of the intercalated discs form a complex network that is chamber dependent and differs between the two sexes. In addition, most HRD genes in atria had higher expression in males than in females, while in ventricles, expression levels were mostly higher in females than in males. Moreover, significant chamber differences were observed between the sexes, with higher expression in atria than ventricles for males and higher expression in ventricles than atria for females. We have ranked the selected genes according to their prominence (new concept) within the HRD gene web defined as extent of expression coordination with the other web genes and stability of expression. Interestingly, the prominence hierarchy was substantially different between the two sexes. Taken together, these findings indicate that the organizational principles of the heart rhythm transcriptome are sex dependent, with the newly introduced prominence analysis allowing identification of genes that are pivotal for the sexual dichotomy.