Genome-wide enhancer maps link disease variants to genes and cell types
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE155555 | GEO | 2021/03/01
REPOSITORIES: GEO
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Project description:Genome-wide association studies (GWAS) have identified thousands of noncoding loci that are associated with human diseases and complex traits, each of which could reveal insights into the mechanisms of disease1. Many of the underlying causal variants may affect enhancers2,3, but we lack accurate maps of enhancers and their target genes to interpret such variants. We recently developed the activity-by-contact (ABC) model to predict which enhancers regulate which genes and validated the model using CRISPR perturbations in several cell types4. Here we apply this ABC model to create enhancer-gene maps in 131 human cell types and tissues, and use these maps to interpret the functions of GWAS variants. Across 72 diseases and complex traits, ABC links 5,036 GWAS signals to 2,249 unique genes, including a class of 577 genes that appear to influence multiple phenotypes through variants in enhancers that act in different cell types. In inflammatory bowel disease (IBD), causal variants are enriched in predicted enhancers by more than 20-fold in particular cell types such as dendritic cells, and ABC achieves higher precision than other regulatory methods at connecting noncoding variants to target genes. These variant-to-function maps reveal an enhancer that contains an IBD risk variant and that regulates the expression of PPIF to alter the membrane potential of mitochondria in macrophages. Our study reveals principles of genome regulation, identifies genes that affect IBD and provides a resource and generalizable strategy to connect risk variants of common diseases to their molecular and cellular functions.
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Project description:Although GWASs have identified thousands of variants associated with human complex traits, most of which reside in the non-coding regions, especially enhancers, and biological mechanisms remain unclear. To created enhancer-gene maps to determine causal variant of CRC risk, we performed multi-omics analyses of ATAC-seq, H3K27ac ChIP-seq and RNA-seq with high quality from our 10 CRC tissues.
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Project description:Genome-wide enhancer maps link disease variants to genes and cell types
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Project description:Mammalian genomes harbor millions of noncoding elements called enhancers that quantitatively regulate gene expression, but the mechanisms that determine which enhancers regulate which genes are not well understood. Here we describe a high-throughput approach, based on CRISPR interference, RNA FISH, and flow cytometry (CRISPRi-FlowFISH), to perturb enhancers in the genome and apply it to test >3,000 potential regulatory enhancer-gene connections across multiple genomic loci. Seemingly complex patterns of enhancer-gene connections in this dataset can largely be explained by a simple quantitative Activity-by-Contact (ABC) model, in which the effect of a candidate enhancer on a target gene is predicted by the intrinsic activity of the enhancer multiplied by the contact frequency between the enhancer and promoter. This ABC score can identify regulatory enhancer-gene connections and predict their quantitative effects from DNase-Seq, H3K27ac ChIP-seq, and Hi-C measurements. The ABC model can explain even complex regulatory phenomena including the ability of an enhancer to “skip” over one gene to regulate a more distant one. Our approach provides a foundation for dissecting mechanisms of enhancer-gene regulation and predicting enhancer-gene connections across cell types.
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