Regulation of Sex-biased Gene Expression by the Ancestral X-Y Chromosomal Gene Pair .

Conventionally, Y-linked is thought to drive sex differences by triggering differential hormone production. Ancestral X-Y gene pairs, however, are hypothesized to drive hormone-independent sex differences. Here, we show that the X-Y gene pair regulates sex-biased gene expression in pluripotent mouse embryonic stem cells (ESCs). Wild-type (WT) XX female ESCs exhibit >2-fold higher expression of 409 genes relative to WT XY male ESCs. Conversely, WT XY male ESCs exhibit >2-fold higher expression of 126 genes compared to WT XX female ESCs. Loss of in female ESCs downregulates female-biased genes. In contrast, loss of either or in male ESCs upregulates female-biased genes and downregulates male-biased genes, effectively neutralizing sex-biased gene expression. KDM5C promotes the expression of and several other Y-linked genes in male ESCs. Moreover, ectopic expression in female ESCs is sufficient to drive male-biased gene expression. These results establish as critical regulators of sex-biased gene expression.