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.
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'.
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