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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE222768 | GEO | 2023/01/17

REPOSITORIES: GEO

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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: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.

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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

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-01-17 | GSE222770 | GEO

Genetic variants that impact alternative polyadenylation in cancer represent candidate causal risk loci [RNA-seq]

Project description:Alternative polyadenylation (APA) is emerging as a major mechanism of post-transcriptional regulation. APA can impact the development and progression of cancer, suggesting that the genetic determinants of APA might play an important role in regulating cancer risk. Here, we depicted a pan-cancer atlas of human APA quantitative trait loci (apaQTLs), containing approximately 0.7 million apaQTLs across 32 cancer types. Systematic multi-omics analyses indicated that cancer apaQTLs could contribute to APA regulation by altering poly(A) motifs, RNA binding proteins (RBP), and chromatin regulatory elements and were preferentially enriched in GWASidentified cancer susceptibility loci. Moreover, apaQTL-related genes (aGenes) were broadly related to cancer signaling pathways, high mutational burden, immune infiltration, and drug response, implicating their potential as therapeutic targets. Furthermore, apaQTLs were mapped in Chinese colorectal cancer (CRC) tumor tissues and then screened for functional apaQTLs associated with CRC risk in 17,789 cases and 19,951 controls using GWAS-ChIP data, with independent validation in a large-scale population consisting of 6,024 cases and 10,022 controls. A multi-ancestry-associated apaQTL variant rs1020670 with a C>G change in DNM1L was identified, and the G allele contributed to an increased risk of CRC. Mechanistically, the risk variant promoted aberrant APA and facilitated higher usage of DNM1L proximal poly(A) sites mediated by the RBP CSTF2T, which led to higher expression of DNM1L with a short 3'UTR. This stabilized DNM1L to upregulate its expression, provoking CRC cell proliferation. Collectively, these findings generate a resource for understanding APA regulation and the genetic basis of human cancers, providing insights into cancer etiology.

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A candidate causal variant underlying both enhanced cognitive performance and increased risk of bipolar disorder

Project description:Bipolar disorder is a highly heritable mental illness, but the relevant genetic variants and molecular mechanisms are largely unknown. Recent GWASs have identified an intergenic region associated with both cognitive performance and bipolar disorder. This region contains dozens of putative fetal brain-specific enhancers and is located ~0.7 Mb upstream of the neuronal transcription factor POU3F2. We identified a candidate causal variant, rs77910749, that falls within a highly conserved putative enhancer, LC1. This human-specific variant is a single-base deletion in a PAX6 binding site and is predicted to be functional. We hypothesized that rs77910749 alters LC1 activity and hence POU3F2 expression during neurodevelopment. Indeed, transgenic reporter mice demonstrated LC1 activity in the developing cerebral cortex and amygdala. Furthermore, ex vivo reporter assays in embryonic mouse brain and human iPSC-derived cerebral organoids revealed increased enhancer activity conferred by the variant. To probe the in vivo function of LC1, we deleted the orthologous mouse region, which resulted in amygdala-specific changes in Pou3f2 expression. Lastly, ‘humanized’ rs77910749 knock-in mice displayed behavioral defects in sensory gating, an amygdala-dependent endophenotype seen in patients with bipolar disorder. Our study suggests a molecular mechanism underlying the long-speculated link between enhanced cognitive performance and neuropsychiatric disease.

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Genetic risk variants for brain disorders are enriched in cortical H3K27ac domains.

Project description: Not available

| S-EPMC6348673 | biostudies-literature

cis-Expression QTL Analysis of Established Risk Variants for Colorectal Cancer

Project description:Genome-wide association studies (GWAS) have identified 19 risk variants associated with colorectal cancer. As most of these risk variants reside outside the coding regions of genes, we conducted cis-expression quantitative trait loci (cis-eQTL) analyses to investigate possible regulatory functions on the expression of neighboring genes. Forty microsatellite stable and CpG island methylator phenotype-negative colorectal tumors and paired adjacent-normal colon tissues were used for genome-wide SNP and gene expression profiling in our cis-eQTL analyses. This submission represents transcriptome component of study.

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cis-Expression QTL Analysis of Established Risk Variants for Colorectal Cancer

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Causal Genetic Variation Underlying Metabolome Differences.

Project description: Not available

| S-EPMC5560816 | biostudies-other

Human iPSC-derived retinal pigment epithelium: a model system for identifying and functionally characterizing causal variants at AMD risk loci

Project description:We evaluate whether human induced pluripotent stem cell-derived retinal pigment epithelium (iPSC-RPE) cells can be used to prioritize and functionally characterize causal variants at age-related macular degeneration (AMD) risk loci. We generated iPSC-RPE from six subjects and show that they have morphological and molecular characteristics similar to native RPE. We generated RNA-seq, ATAC-seq, and H3K27ac ChIP-seq data and observe high similarity in gene expression and enriched transcription factor motif profiles between iPSC-RPE and human fetal-RPE. We performed fine-mapping of AMD risk loci by integrating molecular data from the iPSC-RPE, adult retina, and adult RPE, which identified rs943080 as the probable causal variant at VEGFA. We show that rs943080 is associated with altered chromatin accessibility of a distal ATAC-seq peak, decreased overall gene expression of VEGFA, and allele specific expression of a non-coding transcript. These results provide insight into the mechanism underlying the association of the VEGFA locus with AMD. Raw data requires controlled access and is deposited at dbGaP http://www.ncbi.nlm.nih.gov/gap/?term=phs000924

2019-03-30 | GSE126847 | GEO

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