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Genome-wide enhancer-gene regulatory maps link causal variants to target genes underlying human colorectal cancer risk

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE222770 | GEO | 2023/01/17

REPOSITORIES: GEO

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Genome-wide enhancer-gene regulatory maps link causal variants to target genes underlying human cancer risk.

Project description:Genome-wide association studies have identified numerous variants associated with human complex traits, most of which reside in the non-coding regions, but biological mechanisms remain unclear. However, assigning function to the non-coding elements is still challenging. Here we apply Activity-by-Contact (ABC) model to evaluate enhancer-gene regulation effect by integrating multi-omics data and identified 544,849 connections across 20 cancer types. ABC model outperforms previous approaches in linking regulatory variants to target genes. Furthermore, we identify over 30,000 enhancer-gene connections in colorectal cancer (CRC) tissues. By integrating large-scale population cohorts (23,813 cases and 29,973 controls) and multipronged functional assays, we demonstrate an ABC regulatory variant rs4810856 associated with CRC risk (Odds Ratio = 1.11, 95%CI = 1.05-1.16, P = 4.02 × 10-5) by acting as an allele-specific enhancer to distally facilitate PREX1, CSE1L and STAU1 expression, which synergistically activate p-AKT signaling. Our study provides comprehensive regulation maps and illuminates a single variant regulating multiple genes, providing insights into cancer etiology.

| S-EPMC10520073 | biostudies-literature

Genome-wide enhancer-gene regulatory maps link causal variants to target genes underlying human colorectal cancer risk [RNA-seq]

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. By computationally integrating these multi-omics data, we identified 34,130 enhancer-gene connections involving 15,121 unique enhancers and 12,351 expressed genes. We demonstrated an ABC regulatory variant rs4810856 that is significantly associated with an increased CRC risk with large-scale population study and biological experiments. Our study provides regulation maps linking enhancers to genes, providing new insights into colorectal cancer etiology.

2023-01-17 | GSE222769 | GEO

Genome-wide enhancer-gene regulatory maps link causal variants to target genes underlying human colorectal cancer risk [ATAC-seq]

2023-01-17 | GSE222766 | GEO

Genome-wide enhancer-gene regulatory maps link causal variants to target genes underlying human colorectal cancer risk [H3K27ac ChIP-seq]

2023-01-17 | GSE222768 | GEO

Genome-wide enhancer-gene regulatory maps link causal variants to target genes underlying human colorectal cancer risk

Project description:Genome-wide enhancer-gene regulatory maps link causal variants to target genes underlying human colorectal cancer risk

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Genome-wide enhancer-gene regulatory maps link causal variants to target genes underlying human colorectal cancer risk [ATAC-seq]

Project description:Genome-wide enhancer-gene regulatory maps link causal variants to target genes underlying human colorectal cancer risk [ATAC-seq]

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Genome-wide enhancer-gene regulatory maps link causal variants to target genes underlying human colorectal cancer risk [RNA-seq]

Project description:Genome-wide enhancer-gene regulatory maps link causal variants to target genes underlying human colorectal cancer risk [RNA-seq]

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Genome-wide enhancer-gene regulatory maps link causal variants to target genes underlying human colorectal cancer risk [H3K27ac ChIP-seq]

Project description:Genome-wide enhancer-gene regulatory maps link causal variants to target genes underlying human colorectal cancer risk [H3K27ac ChIP-seq]

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Genome-wide enhancer maps link risk variants to disease genes.

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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Genome-wide enhancer maps link disease variants to genes and cell types

Project description:We generated ATAC-seq and H3K27ac ChIP-seq data in immortalized immune cancer cell lines to predict enhancer-gene regulation using the ABC model.

2021-03-01 | GSE155555 | GEO

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