Breast epithelial cell type specific enhancers and functional annotation of breast cancer risk loci.

摘要

Breast Cancer (BCa) genome-wide association studies (GWAS) revealed allelic frequency differences between cases and controls at index single nucleotide polymorphisms (SNPs). To date 71 loci have thus been identified and replicated. More than 90% of them are in either introns or intergenic regions. Here we hypothesize that at least some of the SNPs affect the activity of non-coding genomic regulatory regions, such as enhancers.;To identify such elements in terms of nucleosome depletion and surrounding histone modifications, we measured Formaldehyde assisted isolation of regulatory elements (FAIRE) and histone modifications, H3K4me1 and H3K27Ac via ChIP-seq genome-wide in human mammary epithelial cells (HMEC) and MDAMB231 breast cancer epithelial cells. We identified 2000 HMEC specific enhancer loci (HSEL) and 2000 MDAMB231 specific enhancer loci (MSEL), and characterized their enhancer status in terms of poised and active enhancers by annotating histone modifications. Additionally, by analyzing gene expression data in both cells types, we found that the enhancers (identified above) affect nearby gene expression, and this effect was significantly correlated with the enhancer status.;To find possible functional SNPs in 71 BCa risk loci, we extracted all the SNPs, residing in 1Mb windows around breast cancer risk index SNP from the 1000 genomes project to find correlated SNPs as defined by r2. We used FunciSNP, an R/Bioconductor package developed in-house with input from me, to identify potentially functional SNPs at 71 risk loci by coinciding them with chromatin biofeatures, including enhancers. We identified 1,005 SNPs in LD with the index SNPs (r2&