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Structural interaction between DISC1 and ATF4 underlying transcriptional and synaptic dysregulation in an iPSC model of mental disorders

Molecular Psychiatry volume 26, pages 1346–1360 (2021)Cite this article

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Abstract

Psychiatric disorders are a collection of heterogeneous mental disorders arising from a contribution of genetic and environmental insults, many of which molecularly converge on transcriptional dysregulation, resulting in altered synaptic functions. The underlying mechanisms linking the genetic lesion and functional phenotypes remain largely unknown. Patient iPSC-derived neurons with a rare frameshift DISC1 (Disrupted-in-schizophrenia 1) mutation have previously been shown to exhibit aberrant gene expression and deficits in synaptic functions. How DISC1 regulates gene expression is largely unknown. Here we show that Activating Transcription Factor 4 (ATF4), a DISC1 binding partner, is more abundant in the nucleus of DISC1 mutant human neurons and exhibits enhanced binding to a collection of dysregulated genes. Functionally, overexpressing ATF4 in control neurons recapitulates deficits seen in DISC1 mutant neurons, whereas transcriptional and synaptic deficits are rescued in DISC1 mutant neurons with CRISPR-mediated heterozygous ATF4 knockout. By solving the high-resolution atomic structure of the DISC1–ATF4 complex, we show that mechanistically, the mutation of DISC1 disrupts normal DISC1–ATF4 interaction, and results in excessive ATF4 binding to DNA targets and deregulated gene expression. Together, our study identifies the molecular and structural basis of an DISC1–ATF4 interaction underlying transcriptional and synaptic dysregulation in an iPSC model of mental disorders.

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Acknowledgements

We thank members of Ming and Song laboratories for discussion, D. Johnson and B. Temsamrit for technical support, J. Schnoll for lab coordination. This work was a component of the National Cooperative Reprogrammed Cell Research Groups (NCRCRG) to Study Mental Illness and was supported by the National Institutes of Health (NIH) grant to G-lM and HS (U19MH106434). Additional supports were by grants from RGC of Hong Kong (664113, AoE-M09-12, C6004-17G, T13-607/12 R, and T13-605/18 W to MZ; 16104518 to FY) and National Key R&D Program of China (2016YFA0501903 to MZ), and grants from NIH (P01NS097206 and R37NS047344 to HS, R35NS097370 and R01MH105128 to G-lM). MZ is a Kerry Holdings Professor in Science and a Senior Fellow of IAS at HKUST.

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Author notes

  1. These authors contributed equally: Xinyuan Wang, Fei Ye

Authors and Affiliations

  1. School of Basic Medical Sciences, Fudan University, 200032, Shanghai, China

    Xinyuan Wang & Guomin Zhou

  2. Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Xinyuan Wang, Ziyuan Guo, Wei-Kai Huang, Yijing Su, Kimberly M. Christian, Hongjun Song & Guo-li Ming

  3. Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China

    Fei Ye, Chuan Yu & Mingjie Zhang

  4. Center of Systems Biology and Human Health, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China

    Fei Ye & Mingjie Zhang

  5. Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, 30322, USA

    Zhexing Wen

  6. Department of Cell Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA

    Zhexing Wen

  7. Pathology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Wei-Kai Huang

  8. The Human Genetics Pre-doctoral Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Francisca Rojas Ringeling

  9. National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, 20892, USA

    Wei Zheng

  10. Department of Cell and Developmental Biology, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Hongjun Song & Guo-li Ming

  11. Institute for Regenerative Medicine, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Hongjun Song & Guo-li Ming

  12. The Epigenetics Institute, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Hongjun Song

  13. Department of Psychiatry, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Guo-li Ming

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  1. Xinyuan Wang
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Contributions

XW and FY co-led the project and contributed equally to this work. ZW, ZG, CY, W-KH, FRR, YS, GZ, and KMC contributed to additional data collection and analyses, WZ contributed reagents, XW, FY, HS, MZ, and GM wrote the paper.

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Correspondence to Hongjun Song, Mingjie Zhang or Guo-li Ming.

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Wang, X., Ye, F., Wen, Z. et al. Structural interaction between DISC1 and ATF4 underlying transcriptional and synaptic dysregulation in an iPSC model of mental disorders. Mol Psychiatry 26, 1346–1360 (2021). https://doi.org/10.1038/s41380-019-0485-2

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