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The Role of KDM2A and H3K36me2 Demethylation in Modulating MAPK Signaling During Neurodevelopment

 Zongyao Ren1 · Haiyan Tang1 · Wendiao Zhang1 · Minghui Guo1 · Jingjie Cui1 · Hua Wang7 · Bin Xie1 · Jing Yu1 · Yonghao Chen1 · Ming Zhang1 · Cong Han1 · Tianyao Chu1 · Qiuman Liang1 · Shunan Zhao1 · Yingjie Huang1 · Xuelian He6 · Kefu Liu1 · Chunyu Liu1,5 · Chao Chen1,2,3,4
1 Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, and Department of Psychiatry, The Second Xiangya Hospital, Central South University, Changsha 410028, China
2 National Clinical Research Center on Mental Disorders, The Second Xiangya Hospital, Central South University, Changsha 410028, China
3 National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410011, China
4 Furong Laboratory, Changsha 410000, China
5 Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY 13210, USA
6 Precision Medical Center, Wuhan Children’s Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430014, China
7 Department of Medical Genetics, Hunan Children’s Hospital, Changsha 410007, China

Abstract
Intellectual disability (ID) is a condition characterized by cognitive impairment and difficulties in adaptive functioning. In our research, we identified two de novo mutations (c.955C>T and c.732C>A) at the KDM2A locus in individuals with varying degrees of ID. In addition, by using the Gene4Denovo database, we discovered five additional cases of de novo mutations in KDM2A. The mutations we identified significantly decreased the expression of the KDM2A protein. To investigate the role of KDM2A in neural development, we used both 2D neural stem cell models and 3D cerebral organoids. Our findings demonstrated that the reduced expression of KDM2A impairs the proliferation of neural progenitor cells (NPCs), increases apoptosis, induces premature neuronal differentiation, and affects synapse maturation. Through ChIP-Seq analysis, we found that KDM2A exhibited binding to the transcription start site regions of genes involved in neurogenesis. In addition, the knockdown of KDM2A hindered H3K36me2 binding to the downstream regulatory elements of genes. By integrating ChIP-Seq and RNA-Seq data, we made a significant discovery of the core genes' remarkable enrichment in the MAPK signaling pathway. Importantly, this enrichment was specifically linked to the p38 MAPK pathway. Furthermore, disease enrichment analysis linked the differentially-expressed genes identified from RNA-Seq of NPCs and cerebral organoids to neurodevelopmental disorders such as ID, autism spectrum disorder, and schizophrenia. Overall, our findings suggest that KDM2A plays a crucial role in regulating the H3K36me2 modification of downstream genes, thereby modulating the MAPK signaling pathway and potentially impacting early brain development.

Keywords
Intellectual disability; KDM2A; Neurodevelopmental disorder; Cerebral organoids