Sex-specific differential gene expression changes in human -iPS Cell-derived myoblasts

Various complex phenotypes in humans, such as disease prevalence, progression, age of onset, and anthropometric traits exhibit sex-differentiated characteristics. These sex-specific differences are often attributed to hormones, sex chromosomes, differences in environmental exposures and behavior, but their underlying molecular mechanism largely remains unknown. The aim of our study was to uncover the cell autonomous gene expression changes between men and women using human induced pluripotent stem cell (iPSC) derived from 8 male donors and 8 female donors that were differentiated into myoblasts (iMyos). Principal component analysis of the overall transcriptomics data revealed distinct gene expression changes in cells taken from male donors as compared to the female donors.

Indeed, we observed 766 genes higher in cells from male donors and 786 genes higher in cells from female donors (FDR<0.2). The male dominant genes were related to the extracellular matrix organization pathways, while the female dominant genes belonged to senescence and cellular stress pathways (p<0.05). Positional enrichment analysis of the most changed male dominant 243 genes and female dominant 497 genes (p<0.05, FC>1.5) showed that only 7% of the differentially expressed genes were encoded by the X- or Y-chromosomes, while the remainder were spread across the autosomes. We also found that these changes were not due to differences in X chromosome dosage in males and females but represent either persistent epigenetic changes and/or crosstalk between X and Y encoded genes and autosomal genes. More importantly, these sex-dependent differences occurred in vitro in a setting in which male and female cells were in identical tissue culture media and without the addition of sex hormones, thus showing cell autonomous sex-specific gene expression changes. Thus, our study highlights an important contribution of sex in exerting gene expression changes, which might further impact physiology and disease.