title: Effect of estrogen receptor α binding on functional DNA methylation in breast cancer.
abstract: Epigenetic modifications introduce an additional layer of regulation that drastically expands the instructional capability of the human genome. The regulatory consequences of DNA methylation is context dependent; it can induce, enhance, and suppress gene expression, or have no effect on gene regulation. Therefore, it is essential to account for the genomic location of its occurrence and the protein factors it associates with to improve our understanding of its function and effects. Here, we use ENCODE ChIP-seq and DNase I hypersensitivity data, along with large-scale breast cancer genomic data from The Cancer Genome Atlas (TCGA) to computationally dissect the intricacies of DNA methylation in regulation of cancer transcriptomes. In particular, we identified a relationship between estrogen receptor α (ERα) activity and DNA methylation patterning in breast cancer. We found compelling evidence that methylation status of DNA sequences at ERα binding sites is tightly coupled with ERα activity. Furthermore, we predicted several transcription factors including FOXA1, GATA1, and SUZ12 to be associated with breast cancer by examining the methylation status of their binding sites in breast cancer. Lastly, we determine that methylated CpGs highly correlated with gene expression are enriched in regions 1kb or more downstream of TSSs, suggesting more significant regulatory roles for CpGs distal to gene TSSs. Our study provides novel insights into the role of ERα in breast cancers.
authors.affiliation: Department of Genetics; Geisel School of Medicine at Dartmouth; Hanover, NH USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Ung
authors.affiliation: Department of Molecular and Cell Biology; Center for Systems Biology; The University of Texas at Dallas; Dallas, TX USA.
authors.forename: Xiaotu
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Community and Family Medicine; Section of Biostatistics and Epidemiology; Geisel School of Medicine at Dartmouth; Lebanon, NH USA; Department of Pharmacology and Toxicology; Geisel School of Medicine at Dartmouth; Hanover, NH USA.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Johnson
authors.affiliation: Department of Community and Family Medicine; Section of Biostatistics and Epidemiology; Geisel School of Medicine at Dartmouth; Lebanon, NH USA; Department of Pharmacology and Toxicology; Geisel School of Medicine at Dartmouth; Hanover, NH USA.
authors.forename: Brock C
authors.initials: BC
authors.lastname: Christensen
authors.affiliation: Department of Genetics; Geisel School of Medicine at Dartmouth; Hanover, NH USA; Institute for Quantitative Biomedical Sciences; Geisel School of Medicine at Dartmouth; Lebanon, NH USA; Norris Cotton Cancer Center; Geisel School of Medicine at Dartmouth; Lebanon, NH USA.
authors.forename: Chao
authors.initials: C
authors.lastname: Cheng
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D018899:CpG Islands; D019175:DNA Methylation; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D050982:GATA1 Transcription Factor / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics; D006801:Humans; D009363:Neoplasm Proteins; D063151:Polycomb Repressive Complex 2 / Q000235:genetics; D014157:Transcription Factors; D059467:Transcriptome
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C496499:FOXA1 protein, human; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D009363:Neoplasm Proteins; C430461:SUZ12 protein, human; D014157:Transcription Factors; D063151:Polycomb Repressive Complex 2
keywords: ChIP-seq; DNase I hypersensitivity; breast cancer; differential gene expression; differential methylation; estrogen receptor α; transcription factor