Mouse anti-Human JMJD1C monoclonal antibody, clone 6G23

Purpose: Autism spectrum disorders are associated with defects in social response and communication that often occur in the context of intellectual disability. Rett syndrome is one example in which epilepsy, motor impairment, and motor disturbance may co-occur. Mutations in histone demethylases are known to occur in several of these syndromes. Herein, we aimed to identify whether mutations in the candidate histone demethylase JMJD1C (jumonji domain containing 1C) are implicated in these disorders. Methods: We performed the mutational and functional analysis of JMJD1C in 215 cases of autism spectrum disorders, intellectual disability, and Rett syndrome without a known genetic defect. Results: We found seven JMJD1C variants that were not present in any control sample (similar to 6,000) and caused an amino acid change involving a different functional group. From these, two de novo JMJD1C germline mutations were identified in a case of Rett syndrome and in a patient with intellectual disability. The functional study of the JMJD1C mutant Rett syndrome patient demonstrated that the altered protein had abnormal subcellular localization, diminished activity to demethylate the DNA damage-response protein MDC1, and reduced binding to MECP2. We confirmed that JMJD1C protein is widely expressed in brain regions and that its depletion compromises dendritic activity. Conclusions: Our findings indicate that mutations in JMJD1C contribute to the development of Rett syndrome and intellectual disability.

Differentiation of adipocytes is a highly regulated process modulated by multiple transcriptional co-activators and co-repressors. JMJD1C belongs to the family of jumonji C (jmjC) domain-containing histone demethylases and was originally described as a ligand-dependent co-activator of thyroid hormone and androgen receptors. Here, we explored the potential role of Jmjdlc in white adipocyte differentiation. To investigate the relevance of Jmjdlc in adipogenesis, murine 3T3-L1 preadipocyte cells with transient knock-down of Jmjdlc (3T3_Jmjdlc) were generated. Depletion of Jmjdlc led to the formation of smaller lipid droplets, reduced accumulation of triglycerides and maintenance of a more fibroblast-like morphology after adipocyte differentiation. Concomitantly, insulin stimulated uptake of glucose and fatty acids was significantly reduced in 3T3_Jmjdlc adipocytes. In line with these observations we detected lower expression of key genes associated with lipid droplet formation (Plinl, Plin4, Cidea) and uptake of glucose and fatty acids (Glut4, Fatpl, Fatp4, Aqp7) respectively. Finally, we demonstrate that depletion of Jmjdlc interferes with mitotic clonal expansion (MCE), increases levels of H3K9me2 (dimethylation of lysine 9 of histone H3) at promotor regions of adipogenic transcription factors (C/EBPs and PPARy) and leads to reduced induction of these key regulators. In conclusion, we have identified Jmjdlc as a modulator of adipogenesis. Our data suggest that Jmjdlc may participate in MCE and the activation of the adipogenic transcription program during the induction phase of adipocyte differentiation in 3T3-L1 cells.