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


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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  1. 1.

    Weinberger DR. Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry. 1987;44:660–9.

  2. 2.

    Mirnics K, Middleton FA, Lewis DA, Levitt P. Analysis of complex brain disorders with gene expression microarrays: schizophrenia as a disease of the synapse. Trends Neurosci. 2001;24:479–86.

  3. 3.

    Birnbaum R, Weinberger DR. Genetic insights into the neurodevelopmental origins of schizophrenia. Nat Rev Neurosci. 2017;18:727–40.

  4. 4.

    Sullivan PF, Daly MJ, O’Donovan M. Genetic architectures of psychiatric disorders: the emerging picture and its implications. Nat Rev Genet. 2012;13:537–51.

  5. 5.

    Wen Z, Christian KM, Song H, Ming GL. Modeling psychiatric disorders with patient-derived iPSCs. Curr Opin Neurobiol. 2016;36:118–27.

  6. 6.

    Soliman MA, Aboharb F, Zeltner N, Studer L. Pluripotent stem cells in neuropsychiatric disorders. Mol Psychiatry. 2017;22:1241–9.

  7. 7.

    Chubb JE, Bradshaw NJ, Soares DC, Porteous DJ, Millar JK. The DISC locus in psychiatric illness. Mol Psychiatry. 2008;13:36–64.

  8. 8.

    Brandon NJ, Sawa A. Linking neurodevelopmental and synaptic theories of mental illness through DISC1. Nat Rev Neurosci. 2011;12:707–22.

  9. 9.

    Tanaka M, et al. Aggregation of scaffolding protein DISC1 dysregulates phosphodiesterase 4 in Huntington’s disease. J Clin Investig. 2017;127:1438–50.

  10. 10.

    Endo R, et al. TAR DNA-binding protein 43 and disrupted in schizophrenia 1 coaggregation disrupts dendritic local translation and mental function in frontotemporal lobar degeneration. Biol Psychiatry. 2018;84:509–21.

  11. 11.

    Mao Y, et al. Disrupted in schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3beta/beta-catenin signaling. Cell. 2009;136:1017–31.

  12. 12.

    Duan X, et al. Disrupted-in-schizophrenia 1 regulates integration of newly generated neurons in the adult brain. Cell. 2007;130:1146–58.

  13. 13.

    Faulkner RL, et al. Development of hippocampal mossy fiber synaptic outputs by new neurons in the adult brain. Proc Natl Acad Sci USA. 2008;105:14157–62.

  14. 14.

    Hayashi-Takagi A, et al. Disrupted-in-schizophrenia 1 (DISC1) regulates spines of the glutamate synapse via Rac1. Nat Neurosci. 2010;13:327–32.

  15. 15.

    Wang Q, et al. The psychiatric disease risk factors DISC1 and TNIK interact to regulate synapse composition and function. Mol Psychiatry. 2011;16:1006–23.

  16. 16.

    Kim JY, et al. Interplay between DISC1 and GABA signaling regulates neurogenesis in mice and risk for schizophrenia. Cell. 2012;148:1051–64.

  17. 17.

    Seshadri S, et al. Interneuronal DISC1 regulates NRG1-ErbB4 signalling and excitatory-inhibitory synapse formation in the mature cortex. Nat Commun. 2015;6:10118.

  18. 18.

    Camargo LM, et al. Disrupted in schizophrenia 1 interactome: evidence for the close connectivity of risk genes and a potential synaptic basis for schizophrenia. Mol Psychiatry. 2007;12:74–86.

  19. 19.

    Soares DC, Carlyle BC, Bradshaw NJ, Porteous DJ. DISC1: structure, function, and therapeutic potential for major mental illness. ACS Chem Neurosci. 2011;2:609–32.

  20. 20.

    Wilkinson B, et al. Endogenous cell type-specific disrupted in schizophrenia 1 interactomes reveal protein networks associated with neurodevelopmental disorders. Biol Psychiatry. 2018.

  21. 21.

    Shao L, et al. Disrupted-in-schizophrenia-1 (DISC1) protein disturbs neural function in multiple disease-risk pathways. Hum Mol Genet. 2017;26:2634–48.

  22. 22.

    Thomson PA, et al. DISC1 genetics, biology and psychiatric illness. Front Biol. 2013;8:1–31.

  23. 23.

    Ye F, et al. DISC1 regulates neurogenesis via modulating kinetochore attachment of Ndel1/Nde1 during mitosis. Neuron. 2017;96:1041–1054 e1045.

  24. 24.

    Chen A, et al. Inducible enhancement of memory storage and synaptic plasticity in transgenic mice expressing an inhibitor of ATF4 (CREB-2) and C/EBP proteins. Neuron. 2003;39:655–69.

  25. 25.

    Ma T, et al. Suppression of eIF2alpha kinases alleviates Alzheimer’s disease-related plasticity and memory deficits. Nat Neurosci. 2013;16:1299–305.

  26. 26.

    Pasini S, Corona C, Liu J, Greene LA, Shelanski ML. Specific downregulation of hippocampal ATF4 reveals a necessary role in synaptic plasticity and memory. Cell Rep. 2015;11:183–91.

  27. 27.

    Davies G, et al. Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function. Nat Commun. 2018;9:2098.

  28. 28.

    Millar JK, Christie S, Porteous DJ. Yeast two-hybrid screens implicate DISC1 in brain development and function. Biochem Biophys Res Commun. 2003;311:1019–25.

  29. 29.

    Morris JA, Kandpal G, Ma L, Austin CP. DISC1 (Disrupted-In-Schizophrenia 1) is a centrosome-associated protein that interacts with MAP1A, MIPT3, ATF4/5 and NUDEL: regulation and loss of interaction with mutation. Hum Mol Genet. 2003;12:1591–608.

  30. 30.

    Soda T, et al. DISC1-ATF4 transcriptional repression complex: dual regulation of the cAMP-PDE4 cascade by DISC1. Mol Psychiatry. 2013;8:898–908.

  31. 31.

    Sawamura N, et al. Nuclear DISC1 regulates CRE-mediated gene transcription and sleep homeostasis in the fruit fly. Mol Psychiatry. 2008;13:1138–48. 1069

  32. 32.

    Malavasi EL, Ogawa F, Porteous DJ, Millar JK. DISC1 variants 37W and 607F disrupt its nuclear targeting and regulatory role in ATF4-mediated transcription. Hum Mol Genet. 2012;21:2779–92.

  33. 33.

    Wen Z, et al. Synaptic dysregulation in a human iPS cell model of mental disorders. Nature. 2014;515:414–8.

  34. 34.

    Yoon KJ, et al. Modeling a genetic risk for schizophrenia in iPSCs and mice reveals neural stem cell deficits associated with adherens junctions and polarity. Cell Stem Cell. 2014;15:79–91.

  35. 35.

    Kim D, et al. TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol. 2013;14:R36.

  36. 36.

    Anders S, Pyl PT, Huber W. HTSeq–a Python framework to work with high-throughput sequencing data. Bioinformatics. 2015;31:166–9.

  37. 37.

    Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15:550.

  38. 38.

    Huang da W, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009;4:44–57.

  39. 39.

    Wang J, Duncan D, Shi Z, Zhang B. WEB-based GEne SeT anaLysis toolkit (WebGestalt): update 2013. Nucleic Acids Res. 2013;41:W77–83.

  40. 40.

    Wickham H. ggplot2: elegant graphics for data analysis. New York: Springer-Verlag; 2016.

  41. 41.

    Zeng Y, et al. Lin28A binds active promoters and recruits Tet1 to regulate gene expression. Mol Cell. 2016;61:153–60.

  42. 42.

    Ho SY, et al. NeurphologyJ: an automatic neuronal morphology quantification method and its application in pharmacological discovery. BMC Bioinform. 2011;12:230.

  43. 43.

    Shen Y, et al. TALOS+: a hybrid method for predicting protein backbone torsion angles from NMR chemical shifts. J Biomol NMR. 2009;44:213–23.

  44. 44.

    Brunger AT, et al. Crystallography & NMR System (CNS), A new software suite for macromolecular structure determination. Acta Crystallogr D. 1998;54:905–21.

  45. 45.

    Koradi R, et al., MOLMOL: A program for display and analysis of macromolecular structures. J Mol Graphics. 1996;14:51–5.

  46. 46.

    Laskowski RA, et al. AQUA and PROCHECK-NMR: Programs for checking the quality of protein structures solved by NMR. J Biomol NMR. 1996;8:477.

  47. 47.

    Chiang CH, et al. Integration-free induced pluripotent stem cells derived from schizophrenia patients with a DISC1 mutation. Mol Psychiatry. 2011;16:358–60.

  48. 48.

    Sachs NA, et al. A frameshift mutation in disrupted in schizophrenia 1 in an American family with schizophrenia and schizoaffective disorder. Mol Psychiatry. 2005;10:758–64.

  49. 49.

    Chu CT, Plowey ED, Wang Y, Patel V, Jordan-Sciutto KL. Location, location, location: altered transcription factor trafficking in neurodegeneration. J Neuropathol Exp Neurol. 2007;66:873–83.

  50. 50.

    Costa-Mattioli M, et al. eIF2alpha phosphorylation bidirectionally regulates the switch from short- to long-term synaptic plasticity and memory. Cell. 2007;129:195–206.

  51. 51.

    Richter JD, Klann E. Making synaptic plasticity and memory last: mechanisms of translational regulation. Genes Dev. 2009;23:1–11.

  52. 52.

    St Clair D, et al. Association within a family of a balanced autosomal translocation with major mental illness. Lancet. 1990;336:13–16.

  53. 53.

    Genovese G, et al. Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia. Nat Neurosci. 2016;19:1433–41.

  54. 54.

    Kano SI, et al. Host-parasite interaction associated with major mental illness. Mol Psychiatry. 2018.

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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.

Author information

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.

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

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