NYMC Faculty Publications

YBX1-Mediated DNA Methylation-Dependent SHANK3 Expression in Pbmcs and Developing Cortical Interneurons in Schizophrenia

Peiyan Ni, The Mental Health Center and Psychiatric Laboratory, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, P. R. China.
Chuqing Zhou, The Mental Health Center and Psychiatric Laboratory, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, P. R. China.
Sugai Liang, Department of Neurobiology, Affiliated Mental Health Center & Hangzhou Seventh People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China.
Youhui Jiang, The Mental Health Center and Psychiatric Laboratory, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, P. R. China.
Dongxin Liu, Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY, 10595, USA.Follow
Zhicheng Shao, Department of Psychiatry, McLean Hospital/Harvard Medical School, Belmont, MA, 02478, USA.
Haneul Noh, Department of Psychiatry, McLean Hospital/Harvard Medical School, Belmont, MA, 02478, USA.
Liansheng Zhao, The Mental Health Center and Psychiatric Laboratory, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, P. R. China.
Yang Tian, The Mental Health Center and Psychiatric Laboratory, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, P. R. China.
Chengcheng Zhang, The Mental Health Center and Psychiatric Laboratory, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, P. R. China.
Jinxue Wei, The Mental Health Center and Psychiatric Laboratory, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, P. R. China.
Xiaojing Li, The Mental Health Center and Psychiatric Laboratory, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, P. R. China.
Hua Yu, The Mental Health Center and Psychiatric Laboratory, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, P. R. China.
Rongjun Ni, The Mental Health Center and Psychiatric Laboratory, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, P. R. China.
Xueli Yu, Department of Neurobiology, Affiliated Mental Health Center & Hangzhou Seventh People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China.
Xueyu Qi, Department of Neurobiology, Affiliated Mental Health Center & Hangzhou Seventh People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China.
Yamin Zhang, The Mental Health Center and Psychiatric Laboratory, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, P. R. China.
Xiaohong Ma, The Mental Health Center and Psychiatric Laboratory, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, P. R. China.
Wei Deng, Department of Neurobiology, Affiliated Mental Health Center & Hangzhou Seventh People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China.
Wanjun Guo, Department of Neurobiology, Affiliated Mental Health Center & Hangzhou Seventh People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China.
Qiang Wang, The Mental Health Center and Psychiatric Laboratory, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, P. R. China.
Pak C. Sham, Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, 999077, China.
Sangmi Chung, Department of Psychiatry, McLean Hospital/Harvard Medical School, Belmont, MA, 02478, USA.Follow
Tao Li, Department of Neurobiology, Affiliated Mental Health Center & Hangzhou Seventh People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China.

Author Type(s)

Faculty

DOI

10.1002/advs.202300455

Journal Title

Advanced Science

First Page

e2300455

Document Type

Article

Publication Date

7-1-2023

Department

Cell Biology and Anatomy

Abstract

Schizophrenia (SCZ) is a severe psychiatric and neurodevelopmental disorder. The pathological process of SCZ starts early during development, way before the first onset of psychotic symptoms. DNA methylation plays an important role in regulating gene expression and dysregulated DNA methylation is involved in the pathogenesis of various diseases. The methylated DNA immunoprecipitation-chip (MeDIP-chip) is performed to investigate genome-wide DNA methylation dysregulation in peripheral blood mononuclear cells (PBMCs) of patients with first-episode SCZ (FES). Results show that the SHANK3 promoter is hypermethylated, and this hypermethylation (HyperM) is negatively correlated with the cortical surface area in the left inferior temporal cortex and positively correlated with the negative symptom subscores in FES. The transcription factor YBX1 is further found to bind to the HyperM region of SHANK3 promoter in induced pluripotent stem cells (iPSCs)-derived cortical interneurons (cINs) but not glutamatergic neurons. Furthermore, a direct and positive regulatory effect of YBX1 on the expression of SHANK3 is confirmed in cINs using shRNAs. In summary, the dysregulated SHANK3 expression in cINs suggests the potential role of DNA methylation in the neuropathological mechanism underlying SCZ. The results also suggest that HyperM of SHANK3 in PBMCs can serve as a potential peripheral biomarker of SCZ.

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