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

Mol Psychiatry. 2021 Apr;26(4):1346-1360. doi: 10.1038/s41380-019-0485-2.

Xinyuan Wang ^# ¹ ², Fei Ye ^# ³ ⁴, Zhexing Wen ⁵ ⁶, Ziyuan Guo ², Chuan Yu ³, Wei-Kai Huang ² ⁷, Francisca Rojas Ringeling ⁸, Yijing Su ², Wei Zheng ⁹, Guomin Zhou ¹, Kimberly M Christian ², Hongjun Song ¹⁰ ¹¹ ¹² ¹³, Mingjie Zhang ¹⁴ ¹⁵, Guo-Li Ming ¹⁶ ¹⁷ ¹⁸ ¹⁹

Affiliations

1 School of Basic Medical Sciences, Fudan University, 200032, Shanghai, China.
2 Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
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.
4 Center of Systems Biology and Human Health, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
5 Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, 30322, USA.
6 Department of Cell Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA.
7 Pathology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
8 The Human Genetics Pre-doctoral Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
9 National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, 20892, USA.
10 Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. [email protected].
11 Department of Cell and Developmental Biology, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. [email protected].
12 Institute for Regenerative Medicine, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. [email protected].
13 The Epigenetics Institute, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. [email protected].
14 Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China. [email protected].
15 Center of Systems Biology and Human Health, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China. [email protected].
16 Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. [email protected].
17 Department of Cell and Developmental Biology, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. [email protected].
18 Institute for Regenerative Medicine, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. [email protected].
19 Department of Psychiatry, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. [email protected].
# Contributed equally.

PMID: 31444471 DOI: 10.1038/s41380-019-0485-2

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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