The large majority of genomic loci linked to schizophrenia heritability by genome-wide association harbor regulatory non-coding DNA, including enhancers and repressors, that are not bound to the nearest TSS but instead tethered via chromosomal contacts to genes located elsewhere on the chromosome. Therefore, unsurprisingly, `linear genome' based approaches such as gene expression quantitative trait loci (eQTL) and SNP prioritization algorithms have very limited success in assigning specific target genes to risk loci. Guided by recent Hi-C genome-scale chromosomal contact mapping studies by us and others, we will test in this proposal whether the genetic risk architecture of schizophrenia is associated with cell-type specific vulnerabilities as it pertains to the developmental reorganization of the chromosomal connectome. We predict that neuronal specification into glutamatergic, GABAergic and dopaminergic lineages associated with cell-type specific genome-scale prunings of chromosomal contacts and loss of smaller-scaled chromatin domains. This includes the domain protoype of many of the smaller self-folded `topologically-associated domain' (TAD), with the developmental dissolution of many subTADs nested into larger and megadomain TADs. Furthermore, we predict that differentiating neurons show a disproportionate increase in chromosomal contacts anchored in sequences conferring heritable risk for schizophrenia and related cognitive disorders and traits. We will monitor developmentally regulated shufflings of intranuclear positions for specific GWAS loci and predict mportant differences between the various neural cell types isogenically generated from hiPSCs. If so, then the `functional epistasis', or least co-regulation, of subsets of risk loci sharing the same nuclear sub-territory could be highly dependent on cell type. Last but not least, we predict that targeted mobilization of specific chromatin domains by CRISPR-Genome Organization (CRISPR-GO) approaches can be harnessed for simultaneous targeting of multiple GWAS locis to to specific nuclear compartments such as the nuclear lamina or Cajal body, resulting in multi-layered transcriptome and epigenome changes and cell-type specific phenotypic alterations.

Public Health Relevance

To better understand the genetic risk architecture of schizophrenia, a major psychiatric disorder, we will map on a genome-wide scale the developmentally regulated changes in chromosomal conformations across three major neuronal subtypes, and map the position of hundreds of disease-relevant sequences into this `spatial genome'.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH106056-06
Application #
10023272
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Arguello, Alexander
Project Start
2015-01-15
Project End
2024-07-31
Budget Start
2020-08-07
Budget End
2021-07-31
Support Year
6
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Psychiatry
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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Rajarajan, Prashanth; Borrman, Tyler; Liao, Will et al. (2018) Neuron-specific signatures in the chromosomal connectome associated with schizophrenia risk. Science 362:
Mitchell, A C; Javidfar, B; Pothula, V et al. (2018) MEF2C transcription factor is associated with the genetic and epigenetic risk architecture of schizophrenia and improves cognition in mice. Mol Psychiatry 23:123-132
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Girdhar, Kiran; Hoffman, Gabriel E; Jiang, Yan et al. (2018) Cell-specific histone modification maps in the human frontal lobe link schizophrenia risk to the neuronal epigenome. Nat Neurosci 21:1126-1136
Narla, S T; Lee, Y-W; Benson, C A et al. (2017) Common developmental genome deprogramming in schizophrenia - Role of Integrative Nuclear FGFR1 Signaling (INFS). Schizophr Res 185:17-32
Powell, S K; Gregory, J; Akbarian, S et al. (2017) Application of CRISPR/Cas9 to the study of brain development and neuropsychiatric disease. Mol Cell Neurosci 82:157-166
Chatterton, Zac; Hartley, Brigham J; Seok, Man-Ho et al. (2017) In utero exposure to maternal smoking is associated with DNA methylation alterations and reduced neuronal content in the developing fetal brain. Epigenetics Chromatin 10:4
Javidfar, Behnam; Park, Royce; Kassim, Bibi S et al. (2017) The epigenomics of schizophrenia, in the mouse. Am J Med Genet B Neuropsychiatr Genet 174:631-640

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