DNA methylation at enhancers identifies distinct breast cancer lineages

Breast cancers exhibit genome-wide aberrant DNA methylation patterns. To investigate how these affect the transcriptome and which changes are linked to transformation or progression, we apply genome-wide expression-methylation quantitative trait loci (emQTL) analysis between DNA methylation and gene expression. On a whole genome scale, in cis and in trans, DNA methylation and gene expression have remarkably and reproducibly conserved patterns of association in three breast cancer cohorts (n=104, n=253 and n=277). The emQTL associations form two main clusters, one relates to tumor infiltrating immune cell signatures and the other to estrogen receptor signaling. In the estrogen related cluster, using ChromHMM segmentation and transcription factor ChIP-seq data, we identify transcriptional networks regulated in a cell lineage-specific manner by DNA methylation at enhancers. These networks are strongly dominated by ERα, FOXA1 or GATA3 and their targets were functionally validated using knock-down by siRNA or GRO-seq analysis after transcriptional stimulation with estrogen. Bisulphite converted DNA from the 285 samples were hybridized to the Illumina Infinium 450k Human Methylation Beadchip