Human Sex Matters: Y-Linked Lysine Demethylase 5D Drives Accelerated Male Craniofacial Osteogenic Differentiation

Abstract

Female sex is increasingly associated with a loss of bone mass during aging and an increased risk of developing nonunion fractures. Hormonal factors and cell-intrinsic mechanisms are suggested to drive these sexual dimorphisms, although underlying molecular mechanisms are still a matter of debate. Here, we observed a decreased capacity of calvarial bone recovery in female rats and a profound sexually dimorphic osteogenic differentiation in human adult neural crest-derived stem cells (NCSCs). Next to an elevated expression of pro-osteogenic regulators, global transcriptomics revealed Lysine Demethylase 5D (KDM5D) to be highly upregulated in differentiating male NCSCs. Loss of function by siRNA or pharmacological inhibition of KDM5D significantly reduced the osteogenic differentiation capacity of male NCSCs. In summary, we demonstrated craniofacial osteogenic differentiation to be sexually dimorphic with the expression of KDM5D as a prerequisite for accelerated male osteogenic differentiation, emphasizing the analysis of sex-specific differences as a crucial parameter for treating bone defects.

Single cell regulatory architecture of human pancreatic islets suggests sex differences in β cell function and the pathogenesis of type 2 diabetes.

“…KDM5D drives sex differences in male osteogenesis, cardiomyocyte, and cancer. [44][45][46][47] Thus, sex differences in expression of chromatin remodelers like KDM6A or KDM5D may influence sex-specific chromatin access to transcription factors promoting sex differences in islet function. Consistent with this possibility, we observed a five-to-ten-fold greater number of transcription factorspecific accessible motifs in female compared to male α and β cells.…”

Single cell regulatory architecture of human pancreatic islets suggests sex differences in β cell function and the pathogenesis of type 2 diabetes.

“…KDM5D drives sex differences in male osteogenesis, cardiomyocyte, and cancer. [46][47][48][49] Thus, sex differences in expression of chromatin remodelers like KDM6A or KDM5D may influence sex-specific chromatin access to transcription factors promoting sex differences in islet function. Consistent with this possibility, we observed a five-to-ten-fold greater number of transcription factorspecific accessible motifs in female compared to male α and β cells.…”

Colitis Induces Sex-Specific Intestinal Transcriptomic Responses in Mice

“…We also discovered specific and strong sex differences in the expression of three histone lysine demethylases, namely Kdm5c, Kdm5d , and Kdm6a . These genes are all located on the sex chromosomes, and the Y-linked Kdm5d was recently reported to be sex-dependently upregulated also in male neural crest-derived stem cells in rats [ 35 ]. Deregulation of lysine demethylases is frequently observed in cancer [ 36 ], and may thus also contribute to sex differences in tumorigenesis.…”