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

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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.

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Data Availability

RNA-Seq and ChIP-Seq data were deposited in Gene Expression Omnibus (Accession number: GSE229836). All other data associated with this study are shown in the manuscript or Supplementary Materials.

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Acknowledgements

We thank Dr. Xiao Mao and Dr. Li Shu for providing the ID case. We also appreciate the technical support from the NHC Key Laboratory of Birth Defects for Research and Prevention at the Hunan Provincial Maternal and Child Health Care Hospital. This work was 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), and the Postgraduate Scientific Research Innovation Project of Hunan Province (CX20220320).

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Authors and Affiliations

  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

    Zongyao Ren, Haiyan Tang, Wendiao Zhang, Minghui Guo, Jingjie Cui, Bin Xie, Jing Yu, Yonghao Chen, Ming Zhang, Cong Han, Tianyao Chu, Qiuman Liang, Shunan Zhao, Yingjie Huang, Kefu Liu, Chunyu Liu & Chao Chen

  2. National Clinical Research Center on Mental Disorders, The Second Xiangya Hospital, Central South University, Changsha, 410028, China

    Chao Chen

  3. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410011, China

    Chao Chen

  4. Furong Laboratory, Changsha, 410000, China

    Chao Chen

  5. Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY, 13210, USA

    Chunyu Liu

  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

    Xuelian He

  7. Department of Medical Genetics, Hunan Children’s Hospital, Changsha, 410007, China

    Hua Wang

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  1. Zongyao Ren
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  18. Chunyu Liu
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Correspondence to Xuelian He, Kefu Liu, Chunyu Liu or Chao Chen.

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The authors declare that there are no conflicts of interest.

Ethical Approval

Informed consent was obtained from the adult patient and the guardians of the affected children. This study was approved by the Ethics Committee of the Hunan Provincial Maternal and Child Health Care Hospital, Hunan, China (2020-S003). The authors greatly appreciate the support and cooperation of all patients and their families.

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Ren, Z., Tang, H., Zhang, W. et al. The Role of KDM2A and H3K36me2 Demethylation in Modulating MAPK Signaling During Neurodevelopment. Neurosci. Bull. (2023). https://doi.org/10.1007/s12264-023-01161-3

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