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Regulation of TRANK1 by GSK-3 in the brain: unexpected interactions

Molecular Psychiatry volume 26, pages 6109–6111 (2021)Cite this article

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TRANK1 is one of the most robust risk genes for bipolar disorder (BD) through genome-wide association studies (GWAS) and independent replications [1,2,3,4]. Previous studies have also reported significant effects of mood stabilizer (e.g., valproic acid) on TRANK1 expression [1, 5], suggesting its potential role in mechanisms underlying therapeutics of BD. Further studies found that dysregulation of TRANK1 could perturb expression of genes related to neural development and differentiation, as well as synaptic plasticity [3, 5]. Nevertheless, the biological underpinnings of TRANK1 in BD pathogenesis and therapeutic treatment remain largely unclear, despite that a previous study reported the reciprocal relationship between mRNA levels of TRANK1 and HDAC1 [5]. Therefore, further characterization of the interactome of TRANK1, especially between TRANK1 and other pivotal genes relevant to BD, is necessary.

GSK-3 are central regulators in many crucial pathways including Wnt signaling. They could activate/inhibit multiple transcription factors (e.g., β-catenin, TCF4, c-Myc and C/EBP-α) and thereby modulate transcription of numerous downstream genes. We therefore investigated if GSK-3 facilitated the transcription of TRANK1. Briefly, we cloned fragments of the human TRANK1 promoter with different lengths (Fig. S2) into pGL3-basic vector, and transfected U251 cells with these vectors with or without co-transfection of GSK-3β overexpression plasmids. We found that overexpressing GSK-3β significantly increased the activity of the ~600-bp TRANK1 promoter and that of longer TRANK1 promoter sequences encompassing this ~600-bp fragment (Fig. 1G). This result thus confirmed that GSK-3β activated the transcription of TRANK1, probably through transcriptional factors with target binding sequences harbored by this ~600-bp TRANK1 promoter fragment. We further conducted a prediction analysis of this ~600-bp TRANK1 promoter sequence, and found two neighboring binding sites of C/EBP-α (Figure S2), a transcription factor whose DNA binding was known to be affected by GSK-3. To test whether C/EBP-α was involved in the regulation of TRANK1 expression by GSK-3, we performed site-directed mutagenesis to delete the two C/EBP-α binding sites in the ~600-bp TRANK1 promoter fragment and obtained a “mutated” TRANK1 promoter. Luciferase reporter gene assays were then performed in U251 cells transfected with wild-type TRANK1 promoter and the “mutated” TRANK1 promoter, respectively. We found that cells with “mutated” TRANK1 promoter displayed significantly lower luciferase activity compared with those carrying the wild-type promoter (p < 0.0001, Fig. 1H); meanwhile, we noticed that that activation magnitude of wild-type TRANK1 promoter was significantly higher (p < 0.0001, Fig. 1H) than that of the “mutated” one (p < 0.05, Fig. 1H) although GSK-3β increased activities of both promoters. Taken together, C/EBP-α likely participated in the regulation of TRANK1 transcription by GSK-3, but further investigations are still needed as molecules other than C/EBP-α might also play a role in the regulatory interaction between TRANK1 and GSK-3.

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Fig. 1: GSK-3 regulate TRANK1 transcriptional activity and mRNA expression.

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Acknowledgements

This work was supported by grants from National Natural Science Foundation of China (82071534 and 81871067 to HC), and the Innovative Research Team of Science and Technology department of Yunnan Province (2019HC004). The authors sincerely thank Li Hui (Suzhou Guangji Hospital) and Hui-Juan Li (Fudan University) for their assistance and contributions during the experiments and projects. Acknowledgments for the use of expression data from PsychENCODE Consortium and CommonMind Consortium are shown in Supplementary Material.

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  1. Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China

    Hong Chang, Xin Cai, Zhi-Hui Yang, Xiao Xiao & Ming Li

  2. Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, China

    Xin Cai, Zhi-Hui Yang & Ming Li

  3. KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China

    Ming Li

  4. CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China

    Ming Li

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Chang, H., Cai, X., Yang, ZH. et al. Regulation of TRANK1 by GSK-3 in the brain: unexpected interactions. Mol Psychiatry 26, 6109–6111 (2021). https://doi.org/10.1038/s41380-021-01120-2

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