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Unbiased analysis of potential targets of breast cancer susceptibility loci by Capture Hi-C

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摘要 : Genome-wide association studies have identified more than 70 common variants that are associated with breast cancerrisk. Most of these variants map to non-protein-coding regions and several map to gene deserts, regions of several hundredkilobases lacking protein-coding genes.
Abstract: genome-wide association studies have identified more than 70 common variants that are associated with breast cancerrisk. Most of these variants map to non-protein-coding regions and several map to GENE deserts, regions of several hundredkilobases lacking protein-coding genes. We hypothesized that gene deserts harbor long-range regulatory elements thatcan physically interact with target genes to influence their expression. To test this, we developed Capture Hi-C (CHi-C),which, by incorporating a sequence capture step into a Hi-C protocol, allows high-resolution analysis of targeted regionsof the genome. We used CHi-C to investigate long-range interactions at three breast cancer gene deserts mapping to 2q35,8q24.21, and 9q31.2. We identified interaction peaks between putative regulatory elements (‘‘bait fragments’’) within thecaptured regions and ‘‘targets’’ that included both protein-coding genes and long noncoding (lnc) RNAs over distances of 6.6kb to 2.6 Mb. Target protein-coding genes were IGFBP5, KLF4, NSMCE2, and MYC; and target lncRNAs included DIRC3, PVT1,and CCDC26. For one gene desert, we were able to define two SNPs (rs12613955 and rs4442975) that were highly correlatedwith the published risk variant and that mapped within the bait end of an interaction peak. In vivo chip-QPCR data show thatone of these, rs4442975, affects the binding of FOXA1 and implicate this SNP as a putative functional variant. Unbiased analysis of potential targets of breast cancer susceptibility loci by Capture Hi-C Figure 6. functional annotation of bait fragment 82 at the 2q35 capture region. (A) The locations of all SNPs that are correlated (r2 $ 0.1) with thepublished risk SNP (rs13387042) are shown, with the two SNPs that are strongly correlated (r2 $ 0.8) in red. SNPs are aligned with CTCF and RAD21binding sites, active (H3K27ac, H3K4me1, and H3K4me3) and repressive (H3K27me3) histone modification marks (in black) generated in the breastcancer cell line MCF7 by the ENCODE Project and by Frietze et al. (2012), and ESR1 and FOXA1 binding peaks generated in MCF7 (blue), T-47D (green),and ZR75-1 cells (red) by Hurtado et al. (2011). All three breast cancer cell lines are homozygous for the G-allele of rs4442975. (B) Positionweighted matrix(PWM) for HOXB13 binding site. The base position that is altered by rs12613955 is indicated by a red box and the sequence of rs12613955 is shown below.Based on ChIP-seq data in (human) prostate cancer cells (Huang et al. 2014), the consensus sequence is conserved between mouse and man. (C )PWM forFOXA1 binding site with the base position that is altered by rs4442975 indicated by a red box and the sequence of rs4442975 shown below. 原文链接:http://www.ncbi.nlm.nih.gov/pubmed/25122612 作者:广州赛诚生物 点击:
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