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

作　　者：Zongyao Ren Haiyan Tang Wendiao Zhang Minghui Guo Jingjie Cui Hua Wang Bin Xie Jing Yu Yonghao Chen Ming Zhang Cong Han Tianyao Chu Qiuman Liang Shunan Zhao Yingjie Huang Xuelian He Kefu Liu Chunyu Liu Chao Chen 

机构地区：[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

出　　处：《Neuroscience Bulletin》2024年第8期1076-1092,共17页神经科学通报（英文版）

基　　金：supported by the National Natural Science Foundation of China(82022024,31970572,and 31871276);the National Key R&D Project of China(2016YFC1306000 and 2017YFC0908701);the Innovation-driven Project of Central South University(2020CX003);The Natural Science Foundation of Hunan Province(2023JJ40793);NIH grants(U01 MH122591,1U01MH116489,and 1R01MH110920);the Postgraduate Scientific Research Innovation Project of Hunan Province(CX20220320).

摘　　要：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.

关 键 词：Intellectual disability KDM2A Neurodevelopmental disorder Cerebral organoids 

分 类 号：R741[医药卫生—神经病学与精神病学]