Sex-Dependent Gene Expression in Human Pluripotent Stem Cells

• The male-specific gene SRY is expressed in male human ESCs and iPSCs
• SRY promoter can be activated in the pluripotent state regardless of sex
• Male and female pluripotent cells differ in autosomal gene expression
• SRY induces differential utilization of cholesterol to produce sex steroids

SummaryMales and females have a variety of sexually dimorphic traits, most of which result from hormonal differences. However, differences between male and female embryos initiate very early in development, before hormonal influence begins, suggesting the presence of genetically driven sexual dimorphisms. By comparing the gene expression profiles of male and X-inactivated female human pluripotent stem cells, we detected Y-chromosome-driven effects. We discovered that the sex-determining gene SRY is expressed in human male pluripotent stem cells and is induced by reprogramming. In addition, we detected more than 200 differentially expressed autosomal genes in male and female embryonic stem cells. Some of these genes are involved in steroid metabolism pathways and lead to sex-dependent differentiation in response to the estrogen precursor estrone. Thus, we propose that the presence of the Y chromosome and specifically SRY may drive sex-specific differences in the growth and differentiation of pluripotent stem cells.

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