Deletion of the X chromosome gene Kdm6a in microglia is protective in the multiple sclerosis model

Multiple sclerosis (MS) exhibits a sex difference in susceptibility with females affected more frequently than males. Sexual dimorphisms may be due to differences in sex hormones, sex chromosomes, or both. Regarding sex chromosomes, some X chromosome genes escape X-inactivation and have higher expression in females (XX) compared to males (XY). The Genotype Tissue Expression Project (GTEx) has found that 37% of all genes exhibit sex biased expression which is tissue-specific and cell-specific, but the etiology and ramifications of this sex difference remain unknown. Kdm6a is an X chromosome gene that escapes X-inactivation and encodes for a histone demethylase which can modulate autosomal gene expression. Given the important role of microglia in neurodegenerative diseases, we created a tissue-specific and cell-specific conditional knock out (cKO) of Kdm6a in microglia and induced experimental autoimmune encephalomyelitis (EAE), the most widely used mouse model for MS. Deletion of Kdm6a in microglia ameliorated EAE. Gene expression analysis of spinal cord microglia during EAE in the Kdm6a cKO revealed downregulation of degeneration associated microglial markers and upregulation of resting microglial markers compared to EAE in wild type. Genome wide transcriptome analyses demonstrated reversal of the EAE associated transcriptome in microglia in Kdm6a cKO mice, instead aligning with that of the transcriptome of microglia in healthy mice. Finally, there was a sex difference in the effect of selective deletion of Kdm6a in microglia whereby EAE was abrogated in females more significantly than in males. Together, this demonstrates that the X-escapee Kdm6a is disease promoting in microglia of females with neurodegenerative disease.