title: Cell-type specific DNA methylation patterns define human breast cellular identity.
abstract: DNA methylation plays a role in a variety of biological processes including embryonic development, imprinting, X-chromosome inactivation, and stem cell differentiation. Tissue specific differential methylation has also been well characterized. We sought to extend these studies to create a map of differential DNA methylation between different cell types derived from a single tissue. Using three pairs of isogenic human mammary epithelial and fibroblast cells, promoter region DNA methylation was characterized using MeDIP coupled to microarray analysis. Comparison of DNA methylation between these cell types revealed nearly three thousand cell-type specific differentially methylated regions (ctDMRs). MassARRAY was performed upon 87 ctDMRs to confirm and quantify differential DNA methylation. Each of the examined regions exhibited statistically significant differences ranging from 10-70%. Gene ontology analysis revealed the overrepresentation of many transcription factors involved in developmental processes. Additionally, we have shown that ctDMRs are associated with histone related epigenetic marks and are often aberrantly methylated in breast cancer. Overall, our data suggest that there are thousands of ctDMRs which consistently exhibit differential DNA methylation and may underlie cell type specificity in human breast tissue. In addition, we describe the pathways affected by these differences and provide insight into the molecular mechanisms and physiological overlap between normal cellular differentiation and breast carcinogenesis.
authors.affiliation: Arizona Cancer Center, The University of Arizona, Tucson, Arizona, USA. petr@umbr.cas.cz
authors.forename: Petr
authors.initials: P
authors.lastname: Novak
authors.forename: Martha R
authors.initials: MR
authors.lastname: Stampfer
authors.forename: Jose L
authors.initials: JL
authors.lastname: Munoz-Rodriguez
authors.forename: James C
authors.initials: JC
authors.lastname: Garbe
authors.forename: Mathias
authors.initials: M
authors.lastname: Ehrich
authors.forename: Bernard W
authors.initials: BW
authors.lastname: Futscher
authors.forename: Taylor J
authors.initials: TJ
authors.lastname: Jensen
mesh_terms: D001940:Breast / Q000166:cytology* / Q000378:metabolism*; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D006657:Histones