Breast cancer risk-associated SNPs modulate the affinity of chromatin for FOXA1 and alter gene expression

Nat Genet. 2012 Nov;44(11):1191-8. doi: 10.1038/ng.2416. Epub 2012 Sep 23.

Abstract

Genome-wide association studies (GWAS) have identified thousands of SNPs that are associated with human traits and diseases. But, because the vast majority of these SNPs are located in non-coding regions of the genome, the mechanisms by which they promote disease risk have remained elusive. Employing a new methodology that combines cistromics, epigenomics and genotype imputation, we annotate the non-coding regions of the genome in breast cancer cells and systematically identify the functional nature of SNPs associated with breast cancer risk. Our results show that breast cancer risk-associated SNPs are enriched in the cistromes of FOXA1 and ESR1 and the epigenome of histone H3 lysine 4 monomethylation (H3K4me1) in a cancer- and cell type-specific manner. Furthermore, the majority of the risk-associated SNPs modulate the affinity of chromatin for FOXA1 at distal regulatory elements, thereby resulting in allele-specific gene expression, which is exemplified by the effect of the rs4784227 SNP on the TOX3 gene within the 16q12.1 risk locus.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Breast Neoplasms / genetics*
  • Chromatin / genetics*
  • Estrogen Receptor alpha / genetics
  • Female
  • Gene Expression Regulation, Neoplastic
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Hepatocyte Nuclear Factor 3-alpha / genetics*
  • High Mobility Group Proteins
  • Histone-Lysine N-Methyltransferase
  • Humans
  • Polymorphism, Single Nucleotide
  • Receptors, Progesterone / genetics*
  • Regulatory Sequences, Nucleic Acid
  • Risk Factors

Substances

  • Chromatin
  • Estrogen Receptor alpha
  • FOXA1 protein, human
  • Hepatocyte Nuclear Factor 3-alpha
  • High Mobility Group Proteins
  • Receptors, Progesterone
  • TOX3 protein, human
  • estrogen receptor alpha, human
  • Histone-Lysine N-Methyltransferase

Associated data

  • GEO/GSE31151