YBX1‐Mediated DNA Methylation‐Dependent SHANK3 Expression in PBMCs and Developing Cortical Interneurons in Schizophrenia

Author:

Ni Peiyan123ORCID,Zhou Chuqing1,Liang Sugai4,Jiang Youhui1,Liu Dongxin3,Shao Zhicheng2,Noh Haneul23,Zhao Liansheng1,Tian Yang1,Zhang Chengcheng1,Wei Jinxue1,Li Xiaojing1,Yu Hua1,Ni Rongjun1,Yu Xueli45,Qi Xueyu45,Zhang Yamin1,Ma Xiaohong1,Deng Wei45,Guo Wanjun45,Wang Qiang1,Sham Pak C.67,Chung Sangmi23,Li Tao45ORCID

Affiliation:

1. The Mental Health Center and Psychiatric Laboratory State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu 610041 P. R. China

2. Department of Psychiatry McLean Hospital/Harvard Medical School Belmont MA 02478 USA

3. Department of Cell Biology and Anatomy New York Medical College Valhalla NY 10595 USA

4. Department of Neurobiology Affiliated Mental Health Center & Hangzhou Seventh People's Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310058 China

5. NHC and CAMS Key Laboratory of Medical Neurobiology MOE Frontier Science Center for Brain Science and Brain‐Machine Integration School of Brain Science and Brain Medicine Zhejiang University Hangzhou Zhejiang 310058 China

6. Department of Psychiatry Li Ka Shing Faculty of Medicine The University of Hong Kong Hong Kong, SAR 999077 China

7. Centre for PanorOmic Sciences The University of Hong Kong Hong Kong, SAR 999077 China

Abstract

AbstractSchizophrenia (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.

Funder

National Natural Science Foundation of China

National Institute of Mental Health

National Institute of Neurological Disorders and Stroke

New York State Stem Cell Science

Publisher

Wiley

Subject

General Physics and Astronomy,General Engineering,Biochemistry, Genetics and Molecular Biology (miscellaneous),General Materials Science,General Chemical Engineering,Medicine (miscellaneous)

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