Erosion of somatic tissue identity with loss of the X-linked intellectual disability factor KDM5C

Mutations in numerous chromatin-modifying enzymes cause neurodevelopmental disorders (NDDs) with unknown mechanisms. Loss of repressive chromatin regulators can lead to the aberrant transcription of tissue-specific genes outside of their intended context, however the mechanisms and consequences of their dysregulation are largely unknown. Here, we examine how lysine demethylase 5c (KDM5C), an eraser of histone 3 lysine 4 di and tri-methylation (H3K4me2/3) that is mutated in Claes-Jensen X-linked intellectual disability, contributes to tissue identity. We found male Kdm5c knockout (-KO) mice, which recapitulate key human neurological phenotypes, aberrantly expresses many liver, muscle, ovary, and testis genes within the amygdala and hippocampus. Gonad-enriched genes misexpressed in the Kdm5c-KO brain are unique to germ cells, indicating an erosion of the soma-germline boundary. Germline genes are typically decommissioned in somatic lineages in the post-implantation epiblast, yet Kdm5c-KO epiblast-like cells (EpiLCs) aberrantly expressed key regulators of germline identity and meiosis, including Dazl and Stra8. Germline gene repression is sexually dimorphic, as female EpiLCs required a higher dose of KDM5C to maintain germline gene suppression. Using a comprehensive list of mouse germline-enriched genes, we found KDM5C is selectively recruited to a subset of germline gene promoters that contain CpG islands (CGIs) to facilitate DNA CpG methylation (CpGme) during ESC to EpiLC differentiation. However, late stage spermatogenesis genes devoid of promoter CGIs can also become activated in Kdm5c-KO cells via ectopic activation by RFX transcription factors. Together, these data demonstrate KDM5C's fundamental role in tissue identity and indicate that KDM5C acts as a break against runaway activation of germline developmental programs in somatic lineages.