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Transcription factor POU3F2 regulates TRIM8 expression contributing to cellular functions implicated in schizophrenia

Molecular Psychiatry volume 26, pages 3444–3460 (2021)Cite this article

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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.

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Fig. 1: POU3F2 regulates SCZ-related genes involved in neural development.
Fig. 2: POU3F2 may affect TRIM8 expression through three SCZ-related SNPs.
Fig. 3: POU3F2 promoted TRIM8 expression through the regulatory SNP rs5011218.
Fig. 4: Silencing POU3F2 and TRIM8 promote NPCs proliferation through advancing cell cycle progression.
Fig. 5: Suppressing POU3F2 and TRIM8 expression inhibited neuronal differentiation and excitatory synaptic transmission.

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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).

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Authors and Affiliations

  1. 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

  2. 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

  3. Department of Neuroscience and Physiology, State University of New York Upstate Medical University, Syracuse, NY, USA

    Chunling Zhang

  4. Guangxi Clinical Research Center for Neurological Diseases, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China

    Qingtuan Meng

  5. Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical University, Guilin, Guangxi, China

    Qingtuan Meng

  6. Child Health Institute of New Jersey, Department of Neuroscience and Cell Biology, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, USA

    Le Wang

  7. Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA

    Yi Jiang

  8. School of Psychology, Shaanxi Normal University, Xi’an, Shaanxi, China

    Chunyu Liu

  9. National Clinical Research Center for Geriatric Disorders, the Xiangya Hospital, Central South University, Changsha, Hunan, China

    Chao Chen

  10. Hunan Key Laboratory of Animal Models for Human Diseases, Central South University, Changsha, Hunan, China

    Chao Chen

  11. Hunan Key Laboratory of Molecular Precision Medicine, Central South University, Changsha, Hunan, China

    Chao Chen

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  1. Chaodong Ding
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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.

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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

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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

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