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

Nicola H Dryden, Laura R Broome, Frank Dudbridge, Nichola Johnson, Nick Orr, Stefan Schoenfelder, Takashi Nagano, Simon Andrews, Steven Wingett, Iwanka Kozarewa, Ioannis Assiotis, Kerry Fenwick, Sarah L Maguire, James Campbell, Rachael Natrajan, Maryou Lambros, Eleni Perrakis, Alan Ashworth, Peter Fraser, Olivia Fletcher

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143 Citations (Scopus)
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Abstract

Genome-wide association studies have identified more than 70 common variants that are associated with breast cancer risk. Most of these variants map to non-protein-coding regions and several map to gene deserts, regions of several hundred kilobases lacking protein-coding genes. We hypothesized that gene deserts harbor long-range regulatory elements that can 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 regions of 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 the captured regions and "targets" that included both protein-coding genes and long noncoding (lnc) RNAs over distances of 6.6 kb 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 correlated with the published risk variant and that mapped within the bait end of an interaction peak. In vivo ChIP-qPCR data show that one of these, rs4442975, affects the binding of FOXA1 and implicate this SNP as a putative functional variant.

Original languageEnglish
Pages (from-to)1854-68
Number of pages15
JournalGenome Research
Volume24
Issue number11
Early online date13 Aug 2014
DOIs
Publication statusPublished - Nov 2014
Externally publishedYes

Keywords

  • Breast Neoplasms
  • Cell Line, Tumor
  • Chromatin Immunoprecipitation
  • Chromosome Mapping
  • Chromosomes, Human, Pair 2
  • Chromosomes, Human, Pair 8
  • Chromosomes, Human, Pair 9
  • Genetic Predisposition to Disease
  • Genome, Human
  • Genome-Wide Association Study
  • Hepatocyte Nuclear Factor 3-alpha
  • Homeodomain Proteins
  • Humans
  • MCF-7 Cells
  • Oligonucleotide Array Sequence Analysis
  • Polymorphism, Single Nucleotide
  • Protein Binding
  • Protein Interaction Mapping
  • RNA, Long Noncoding
  • Real-Time Polymerase Chain Reaction
  • Regulatory Sequences, Nucleic Acid
  • Reproducibility of Results
  • Sequence Analysis, DNA
  • Journal Article
  • Research Support, Non-U.S. Gov't

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