Analysis of Normal Human Mammary Epigenomes Reveals Cell-Specific Active Enhancer States and Associated Transcription Factor Networks

• Published in: Cell reports (Cambridge) Vol. 17; no. 8; pp. 2060 - 2074
• Main Authors: Pellacani, Davide, Bilenky, Misha, Kannan, Nagarajan, Heravi-Moussavi, Alireza, Knapp, David J.H.F., Gakkhar, Sitanshu, Moksa, Michelle, Carles, Annaick, Moore, Richard, Mungall, Andrew J., Marra, Marco A., Jones, Steven J.M., Aparicio, Samuel, Hirst, Martin, Eaves, Connie J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15-11-2016
• Subjects: Adult; Breast - metabolism; Cell Separation; chromatin; Chromatin - metabolism; enhancer; Enhancer Elements, Genetic - genetics; Epigenesis, Genetic; epigenomic; Epithelial Cells - cytology; Epithelial Cells - metabolism; Female; Gene Regulatory Networks; Humans; mammary cells; normal human breast; Phenotype; profiling; Promoter Regions, Genetic; regulatory network; Reproducibility of Results; stem cells; transcription factors; Transcription Factors - metabolism; transcriptome; stem cells; enhancer; normal human breast; regulatory network; profiling; transcription factors; transcriptome; mammary cells; epigenomic; chromatin
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.10.058

The normal adult human mammary gland is a continuous bilayered epithelial system. Bipotent and myoepithelial progenitors are prominent and unique components of the outer (basal) layer. The inner (luminal) layer includes both luminal-restricted progenitors and a phenotypically separable fraction that lacks progenitor activity. We now report an epigenomic comparison of these three subsets with one another, with their associated stromal cells, and with three immortalized, non-tumorigenic human mammary cell lines. Each genome-wide analysis contains profiles for six histone marks, methylated DNA, and RNA transcripts. Analysis of these datasets shows that each cell type has unique features, primarily within genomic regulatory regions, and that the cell lines group together. Analyses of the promoter and enhancer profiles place the luminal progenitors in between the basal cells and the non-progenitor luminal subset. Integrative analysis reveals networks of subset-specific transcription factors.
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•Epigenomes of four normal human breast cell fractions and three cell lines are reported•Luminal progenitor and mature luminal cell epigenomes differ greatly•Enhancers define luminal progenitors as intermediate between basal and luminal cells•Transcription factor binding sites in active enhancers point to distinct regulators
Pellacani et al. present comprehensive histone and DNA modification profiles for four cell types in normal human breast tissue and three immortalized human mammary epithelial cell lines. Analysis of activated enhancers place luminal progenitors in between bipotent progenitor-containing basal cells and nonproliferative luminal cells. Explore consortium data at the Cell Press IHEC webportal at http://www.cell.com/consortium/IHEC.