DNA methylation at enhancers identifies distinct breast cancer lineages

• DOI: 10.1038/s41467-017-00510-x
• Publication Date: 2017-11-03T14:40:21Z
• Authors: Thomas Fleischer; Xavier Tekpli; Anthony Mathelier; Shixiong Wang; Daniel Nebdal; Hari P. Dhakal; Kristine Kleivi S...; Ellen Schlichting; ; Torill Sauer; Jürgen Geisler; Solveig Hofvind; Tone F Bathen; Olav Engebraaten; Øystein Garred; Gry Aarum Geitvik; Anita Langerød; Rolf Kåresen; Gunhild Mari Mæla...; Hege G Russnes; Therese Sørlie; Ole Christian Lin...; Helle Kristine Sk...; Daehoon Park; Britt Fritzman; Anne-Lise Børrese...; Elin Borgen; Bjørn Naume; Ragnhild Eskeland; Arnoldo Frigessi; Jörg Tost; Antoni Hurtado; Vessela N. Kriste...
• Keywords: Hepatocyte Nuclear Factor 3-alpha; 0301 basic medicine; 570; [SDV]Life Sciences [q-bio]; Science; Quantitative Trait Loci; 610; [SDV.CAN]Life Sciences [q-bio]/Cancer; Breast Neoplasms; GATA3 Transcription Factor; Article; Epigenesis, Genetic; 03 medical and health sciences; Humans; Binding Sites; Q; Estrogen Receptor alpha; Reproducibility of Results; DNA Methylation; 3. Good health; Gene Expression Regulation, Neoplastic; Enhancer Elements, Genetic; MCF-7 Cells; CpG Islands; Female; Transcription Factors

AbstractBreast 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 expression–methylation quantitative trait loci 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 chromatin immunoprecipitation sequencing 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 knockdown by small interfering RNA or GRO-seq analysis after transcriptional stimulation with estrogen.