DDX3X and post-transcriptional regulation of cardiac sex differences

About This Grant

PROJECT SUMMARY Congenital heart disease (CHD) is the most common type of congenital malformation [1, 2]. Many CHD conditions exhibit bias based on sex [3-7]. However, there is a significant gap in our understanding of the mechanisms behind these sex-specific differences. In a series of consecutive genetic screens in mice, we identified the X-chromosome gene DEAD-Box Helicase 3 X-Linked (Ddx3x) as regulating male-female cardiac sex differences [8]. DDX3X is expressed in cardiomyocytes and escapes X-inactivation in human hearts [9, 10]. Consistently, we demonstrated that in mice, DDX3X expression is reduced in Turner syndrome (XO) hearts compared to wildtype females (XX) and increased in Klinefelter syndrome (XXY) hearts compared to wildtype males (XY)[3, 8]. Clinical studies have shown that Ddx3x is associated with CHD in females but not males [11-14]. To investigate the cardiac mechanisms associated with the cardiac sex differences related to Ddx3x, we created a conditional allele for Ddx3x. We demonstrated that the deletion of Ddx3x in cardiomyocytes (CM) results in embryonic death accompanied by cardiac desynchrony in female mice but not in male mice by embryonic day (E) 11.5, suggesting that DDX3X plays a function in female cardiac excitation- contraction coupling (ECC). We have gone on to define the endogenous cardiac DDX3X interactome and showed that DDX3X interacts with proteins involved in mRNA translation. We further identified genes essential in ECC as potential DDX3X target mRNAs. Based on our preliminary results, we hypothesize that DDX3X regulates sex-specific mRNA translation that is critical for female cardiac excitation-contraction coupling. 1