The genomic landscape of estrogen receptor α binding sites in mouse mammary gland

• Published in: PloS one 2019-08, Vol.14 (8), p.e0220311-e0220311
• Main Authors: Palaniappan, Murugesan, Nguyen, Loc, Grimm, Sandra L, Xi, Yuanxin, Xia, Zheng, Li, Wei, Coarfa, Cristian
• Format: Article
• Language: English
• Subjects: 17β-Estradiol; Activator protein 1; Animals; Binding sites; Binding Sites - genetics; Biology and Life Sciences; Breast cancer; Cell growth; Cellular biology; Chromatin; Chromatin Immunoprecipitation; Cofactors; Deoxyribonucleic acid; DNA; Elongation; Epithelial cells; Estrogen Receptor alpha - genetics; Estrogen receptors; Estrogens; Female; Gene expression; Gene Expression Profiling; Gene sequencing; Genes; Genome-Wide Association Study; Genomes; Genomics; High-Throughput Nucleotide Sequencing; Immunology; Immunoprecipitation; Interrogation; Ligands; Mammary gland; Mammary glands; Mammary Glands, Animal - metabolism; Medicine; Medicine and Health Sciences; Mice - genetics; Morphogenesis; Next-generation sequencing; Pax2 protein; Proteins; Real-Time Polymerase Chain Reaction; Regulatory sequences; Research and Analysis Methods; Ribonucleic acid; RNA; Sex hormones; Studies; Transcription factors; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0220311

Estrogen receptor α (ERα) is the major driving transcription factor in the mammary gland development as well as breast cancer initiation and progression. However, the genomic landscape of ERα binding sites in the normal mouse mammary gland has not been completely elucidated. Here, we mapped genome-wide ERα binding events by chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) in the mouse mammary gland in response to estradiol. We identified 6237 high confidence ERα binding sites in two biological replicates and showed that many of these were located at distal enhancer regions. Furthermore, we discovered 3686 unique genes in the mouse genome that recruit ER in response to estradiol. Interrogation of ER-DNA binding sites in ER-positive luminal epithelial cells showed that the ERE, PAX2, SF1, and AP1 motifs were highly enriched at distal enhancer regions. In addition, comprehensive transcriptome analysis by RNA-seq revealed that 493 genes are differentially regulated by acute treatment with estradiol in the mouse mammary gland in vivo. Through integration of RNA-seq and ERα ChIP-seq data, we uncovered a novel ERα targetome in mouse mammary epithelial cells. Taken together, our study has identified the genomic landscape of ERα binding events in mouse mammary epithelial cells. Furthermore, our study also highlights the cis-regulatory elements and cofactors that are involved in estrogen signaling and may contribute to ductal elongation in the normal mouse mammary gland.