title: Breast cancer risk-associated SNPs modulate the affinity of chromatin for FOXA1 and alter gene expression.
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.
authors.affiliation: Department of Genetics, Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, New Hampshire, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Cowper-Sal lari
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Zhang
authors.forename: Jason B
authors.initials: JB
authors.lastname: Wright
authors.forename: Swneke D
authors.initials: SD
authors.lastname: Bailey
authors.forename: Michael D
authors.initials: MD
authors.lastname: Cole
authors.forename: Jerome
authors.initials: J
authors.lastname: Eeckhoute
authors.forename: Jason H
authors.initials: JH
authors.lastname: Moore
authors.forename: Mathieu
authors.initials: M
authors.lastname: Lupien
mesh_terms: D000483:Alleles; D051017:Apoptosis Regulatory Proteins; D001943:Breast Neoplasms / Q000235:genetics*; D002843:Chromatin / Q000235:genetics*; D047628:Estrogen Receptor alpha / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics*; D006609:High Mobility Group Proteins; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D011980:Receptors, Progesterone / Q000235:genetics*; D012045:Regulatory Sequences, Nucleic Acid; D012307:Risk Factors; D015534:Trans-Activators
chemical_list: D051017:Apoptosis Regulatory Proteins; D002843:Chromatin; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D006609:High Mobility Group Proteins; D011980:Receptors, Progesterone; C521752:TOX3 protein, human; D015534:Trans-Activators; D011495:Histone-Lysine N-Methyltransferase