Functional Interrogation of Enhancer Connectome Prioritizes Candidate Target Genes at Ovarian Cancer Susceptibility Loci

Abstract

Identifying causal regulatory variants and their target genes from the majority of non-coding disease-associated genetic loci is the main challenge in post-Genome-Wide Association Studies (GWAS) functional studies. Although chromosome conformation capture (3C) and its derivative technologies have been successfully applied to nominate putative causal genes for non-coding variants, many GWAS target genes have not been identified yet. This study generated a high-resolution contact map from epithelial ovarian cancer (EOC) cells with two H3K27ac-HiChIP libraries and analyzed the underlying gene networks for 15 risk loci identified from the largest EOC GWAS. By combinatory analysis of 4,021 fine-mapped credible variants of EOC GWAS and high-resolution contact map, we obtained 162 target genes that mainly enriched in cancer related pathways. Compared with GTEx eQTL genes in ovarian tissue and annotated proximal genes, 132 HiChIP targets were first identified for EOC causal variants. More than half of the credible variants (CVs) involved interactions that were over 185 kb in distance, indicating that long-range transcriptional regulation is an important mechanism for the function of GWAS variants in EOC. We also found that many HiChIP gene targets showed significantly differential expressions between normal ovarian and EOC tumor samples. We validated one of these targets by manipulating the rs9303542 located region with CRISPR-Cas9 deletion and dCas9-VP64 activation experiments and found altered expression of HOXB7 and HOXB8 at 17q21.32. This study presents a systematic analysis to identify putative target genes for causal variants of EOC, providing an in-depth investigation of the mechanisms of non-coding regulatory variants in the etiology and pathogenesis of ovarian cancer.

CRISPR/Cas13-Based Platforms for a Potential Next-Generation Diagnosis of Colorectal Cancer through Exosomes Micro-RNA Detection: A Review

“…Moreover, harnessing CRISPR/Cas9 versatility, it has also been engineered to work as a transcriptional regulator [ 166 ], DNA labeler [ 167 ], and nucleic acid detector [ 168 ]. Thus, the CRISPR/Cas9 toolbox has enabled promising advances, including breast cancer modelling in mice [ 169 ], potential CRISPR-based treatments [ 170 ], interrogation of mechanisms in ovarian cancer [ 171 ], epigenetic control of pancreatic cancer [ 172 ], targeted tumor regression [ 173 ], and lung cancer miRNA detection [ 174 ]. Moreover, CRISPR/Cas technology has recently obtained a considerable milestone in in vivo gene editing to treat transthyretin amyloidosis, achieving the first direct body bloodstream deployment of lipid nanoparticles encapsulating CRISPR/Cas9 mRNA (i.e., Cas9 and gRNA) to safely decline the synthesis of the TTR protein associated with the disease by an average of 87%, whereas conventional methods report up to a 80% TTR synthesis decline [ 175 , 176 , 177 ].…”

Loop Catalog: a comprehensive HiChIP database of human and mouse samples

“…Since the introduction of HiChIP in 2016, the number of publicly available human and mouse HiChIP studies published has consistently increased each year ( Figure 1A ). This indicates the growing popularity of the HiChIP assay, particularly as a method of investigating distal interactions between genetic variants, often in non-coding regions of the genome, and their potential target genes in a cell-type and context-specific manner (V. Chandra et al, 2021; Duan et al, 2021; Giambartolomei et al, 2021; Mumbach et al, 2017; O’Mara et al, 2019; Shi et al, 2021; W. Wang et al, 2021).…”

Identification of lncRNAs Deregulated in Epithelial Ovarian Cancer Based on a Gene Expression Profiling Meta-Analysis

“…The supporting information can be downloaded at: . Complete results of the meta-analysis and references of previous studies [ 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 , 171 , 172 , 173 , 174 ...…”