Transcription factor pou3f2 regulates trim8 expression contributing to cellular functions implicated in schizophrenia

ABSTRACT Schizophrenia (SCZ) is a neuropsychiatric disorder with aberrant expression of multiple genes. However, identifying its exact causal genes remains a considerable challenge. The

brain-specific transcription factor POU3F2 (POU domain, class 3, transcription factor 2) has been recognized as a risk factor for SCZ, but our understanding of its target genes and

pathogenic mechanisms are still limited. Here we report that _POU3F2_ regulates 42 SCZ-related genes in knockdown and RNA-sequencing experiments of human neural progenitor cells (NPCs).

Among those SCZ-related genes, _TRIM8_ (Tripartite motif containing 8) is located in SCZ-associated genetic locus and is aberrantly expressed in patients with SCZ. Luciferase reporter and

electrophoretic mobility shift assays (EMSA) showed that POU3F2 induces _TRIM8_ expression by binding to the SCZ-associated SNP (single nucleotide polymorphism) rs5011218, which affects

POU3F2-binding efficiency at the promoter region of _TRIM8_. We investigated the cellular functions of _POU3F2_ and _TRIM8_ as they co-regulate several pathways related to neural development

and synaptic function. Knocking down either _POU3F2_ or _TRIM8_ promoted the proliferation of NPCs, inhibited their neuronal differentiation, and impaired the excitatory synaptic

transmission of NPC-derived neurons. These results indicate that _POU3F2_ regulates _TRIM8_ expression through the SCZ-associated SNP rs5011218, and both genes may be involved in the

etiology of SCZ by regulating neural development and synaptic function. Access through your institution Buy or subscribe This is a preview of subscription content, access via your

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ACKNOWLEDGEMENTS We thank Glatt’s lab at Upstate Medical University for providing technical support. FUNDING This work was supported by National Natural Science Foundation of China (NSFC)

grants 31970572, 31871276, 31571312, and 81401114, National Key R&D Project of China 2016YFC1306000 and 2017YFC0908701, Innovation-driven Project of Central South University 2020CX003

(to CC) and NIH grants 1U01MH103340, 1U01MH116489, and 1R01MH110920, New York State Empire Innovation Program (to CL). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Center for Medical

Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China Chaodong Ding, Qingtuan Meng, Le Wang, Yan Xia, Yi Jiang, 

Shishi Min, Chunyu Liu & Chao Chen * Department of Psychiatry, State University of New York Upstate Medical University, Syracuse, NY, USA Chaodong Ding, Richard Kopp, Liz Kuney, Yan Xia,

 Rujia Dai, Shishi Min, Wei-Dong Yao, Ma-Li Wong, Hongyu Ruan & Chunyu Liu * Department of Neuroscience and Physiology, State University of New York Upstate Medical University, Syracuse,

NY, USA Chunling Zhang * Guangxi Clinical Research Center for Neurological Diseases, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China Qingtuan Meng * Guangxi Key

Laboratory of Brain and Cognitive Neuroscience, Guilin Medical University, Guilin, Guangxi, China Qingtuan Meng * Child Health Institute of New Jersey, Department of Neuroscience and Cell

Biology, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, USA Le Wang * Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA Yi Jiang *

School of Psychology, Shaanxi Normal University, Xi’an, Shaanxi, China Chunyu Liu * National Clinical Research Center for Geriatric Disorders, the Xiangya Hospital, Central South University,

Changsha, Hunan, China Chao Chen * Hunan Key Laboratory of Animal Models for Human Diseases, Central South University, Changsha, Hunan, China Chao Chen * Hunan Key Laboratory of Molecular

Precision Medicine, Central South University, Changsha, Hunan, China Chao Chen Authors * Chaodong Ding View author publications You can also search for this author inPubMed Google Scholar *

Chunling Zhang View author publications You can also search for this author inPubMed Google Scholar * Richard Kopp View author publications You can also search for this author inPubMed 

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inPubMed Google Scholar * Le Wang View author publications You can also search for this author inPubMed Google Scholar * Yan Xia View author publications You can also search for this author

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author inPubMed Google Scholar * Shishi Min View author publications You can also search for this author inPubMed Google Scholar * Wei-Dong Yao View author publications You can also search

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search for this author inPubMed Google Scholar * Chunyu Liu View author publications You can also search for this author inPubMed Google Scholar * Chao Chen View author publications You can

also search for this author inPubMed Google Scholar CONTRIBUTIONS CL and CC designed and guided the study. CD, LW, and QM performed the gene knockdown, NPC proliferation, dual-luciferase

reporter and neuronal differentiation assays. CZ, YX, YJ, SM, and RD analyzed the RNA-seq data and ran the enrichment analysis. HR did the electrophysiological recordings. CD wrote the

manuscript with substantive edits from RK, LK, MW, WY, CL, and CC. CORRESPONDING AUTHORS Correspondence to Hongyu Ruan, Chunyu Liu or Chao Chen. ETHICS DECLARATIONS CONFLICT OF INTEREST The

authors declare that they have no conflict of interest. ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer Nature remains neutral with regard to jurisdictional claims in published maps and

institutional affiliations. SUPPLEMENTARY INFORMATION SUPPLEMENTARY MATERIALS TABLE S1. 545 COEXPRESSION MODULE GENES TABLE S2. 3,421 GENES WITH EXPRESSION ALTERED BY POU3F2 KNOCKDOWN TABLE

S3. 60 GENES IN COMMON FROM THE 3421 POU3F2-REGULATED GENES AND 545 MODULE GENES TABLE S4. 4,096 DIFFERENTIALLY EXPRESSED GENES FROM PSYCHENCODE TABLE S5. 42 GENES IN COMMON FROM 60

POU3F2-REGULATED MODULE GENES AND 6235 SCZ-RELATED GENES TABLE S6. PREDICTED POU3F2 BINDING SEQUENCES IN THE TRIM8 REGULATORY REGION TABLE S7. EQTL SNPS IN TRIM8’S REGULATORY REGION TABLE

S8. UPSTREAM REGULATORY SEQUENCES OF TRIM8 TABLE S9. EMSA PROBE SEQUENCES TABLE S10. 1040 GENES WITH EXPRESSION ALTERED BY TRIM8 KNOCKDOWN TABLE S11. 548 POU3F2 AND TRIM8 CO-REGULATED GENES

TABLE S12. 202 POU3F2 AND TRIM8 CO-REGULATED SCZ-RELATED GENES TABLE S13. SIGNIFICANTLY ENRICHED PATHWAYS OF POU3F2 AND TRIM8 CO-REGULATED GENES TABLE S14. QPCR PRIMER SEQUENCES RIGHTS AND

PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Ding, C., Zhang, C., Kopp, R. _et al._ Transcription factor POU3F2 regulates _TRIM8_ expression contributing to

cellular functions implicated in schizophrenia. _Mol Psychiatry_ 26, 3444–3460 (2021). https://doi.org/10.1038/s41380-020-00877-2 Download citation * Received: 29 September 2019 * Revised:

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