Abstract
BackgroundEpigenetic regulators are frequently mutated or aberrantly expressed in a variety of cancers, leading to altered transcription states that result in changes in cell identity, behavior, and response to therapy.ResultsTo define alterations in epigenetic landscapes in breast cancers, we profiled the distributions of 8 key histone modifications by ChIP-Seq, as well as primary (GRO-seq) and steady state (RNA-Seq) transcriptomes, across 13 distinct cell lines that represent 5 molecular subtypes of breast cancer and immortalized human mammary epithelial cells.DiscussionUsing combinatorial patterns of distinct histone modification signals, we defined subtype-specific chromatin signatures to nominate potential biomarkers. This approach identified AFAP1-AS1 as a triple negative breast cancer-specific gene associated with cell proliferation and epithelial-mesenchymal-transition. In addition, our chromatin mapping data in basal TNBC cell lines are consistent with gene expression patterns in TCGA that indicate decreased activity of the androgen receptor pathway but increased activity of the vitamin D biosynthesis pathway.ConclusionsTogether, these datasets provide a comprehensive resource for histone modification profiles that define epigenetic landscapes and reveal key chromatin signatures in breast cancer cell line subtypes with potential to identify novel and actionable targets for treatment.
Highlights
Epigenetic regulators are frequently mutated or aberrantly expressed in a variety of cancers, leading to altered transcription states that result in changes in cell identity, behavior, and response to therapy
Together, these datasets provide a comprehensive resource for histone modification profiles that define epigenetic landscapes and reveal key chromatin signatures in breast cancer cell line subtypes with potential to identify novel and actionable targets for treatment
We systematically profiled histone modification patterns and gene expression programs in a set of well characterized cell lines that represent 5 major breast cancer subtypes, including two Estrogen receptor (ER) positive subtypes, Luminal-A and Luminal-B, the human epidermal growth factor receptor 2 (HER2) positive subtype, and two triplenegative subtypes, Triple-negative breast cancer (TNBC)-Claudin Low, and TNBC-Basal, as well as two normal immortalized breast cell lines as controls (Fig. 1a; color codes indicated for each cell line will be used throughout the paper)
Summary
Epigenetic regulators are frequently mutated or aberrantly expressed in a variety of cancers, leading to altered transcription states that result in changes in cell identity, behavior, and response to therapy. Chromatin remodeling factors and histone modifying enzymes are frequently mutated or aberrantly expressed in a wide variety of cancers, leading to altered transcription states that change cell identity, behavior, and response to therapy. Large efforts have systematically profiled epigenomes in various tissue types and diseases, including the ENCODE project [1,2,3] and the Roadmap Epigenomics consortium [4]. We profiled distributions of 8 key histone modifications by ChIP-Seq as well as primary
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