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Genome-scale high-resolution mapping of activating and repressive nucleotides in regulatory regions

ABSTRACT: We employ a massively parallel reporter assay (MPRA) to measure the ex vivo activities in K562 and HepG2 cells of more than 15,000 human candidate regulatory regions. The regulatory regions were tiled with overlapping constructs enabling high resolution computational inference of activating and repressive nucleotides.

ORGANISM(S): Escherichia coli Homo sapiens

PROVIDER: GSE71279 | GEO | 2016/08/12

SECONDARY ACCESSION(S): PRJNA290789

REPOSITORIES: GEO

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Project description:Genome-wide association studies (GWAS) have successfully identified 145 genomic regions that contribute to schizophrenia risk, but linkage disequilibrium (LD) makes it challenging to discern causal variants. Computational finemapping prioritized thousands of credible variants, ~98% of which lie within poorly characterized non-coding regions. To functionally validate their regulatory effects, we performed a massively parallel reporter assay (MPRA) on 5,173 finemapped schizophrenia GWAS variants in primary human neural progenitors (HNPs). We identified 440 variants with allelic regulatory effects (MPRA-positive variants), with 72% of GWAS loci containing at least one MPRA-positive variant. Transcription factor binding had modest predictive power for predicting the allelic activity of MPRA-positive variants, while GWAS association, finemap posterior probability, enhancer overlap, and evolutionary conservation failed to predict MPRA-positive variants. Furthermore, 64% of MPRA-positive variants did not exhibit eQTL signature, suggesting that MPRA could identify yet unexplored variants with regulatory potentials. MPRA-positive variants differed from eQTLs, as they were more frequently located in distal neuronal enhancers. Therefore, we leveraged neuronal 3D chromatin architecture to identify 273 genes that physically interact with MPRA-positive variants. These genes annotated by chromatin interactome displayed higher mutational constraints and regulatory complexity than genes annotated by eQTLs, recapitulating a recent finding that eQTL- and GWAS-detected variants map to genes with different properties. Finally, we propose a model in which allelic activity of multiple variants within a GWAS locus can be aggregated to predict gene expression by taking chromatin contact frequency and accessibility into account. In conclusion, we demonstrate that MPRA can effectively identify functional regulatory variants and delineate previously unknown regulatory principles of schizophrenia.

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Genome-scale high-resolution mapping of activating and repressive nucleotides in regulatory regions

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