title: Age- and pregnancy-associated DNA methylation changes in mammary epithelial cells.
abstract: Postnatal mammary gland development and differentiation occur during puberty and pregnancy. To explore the role of DNA methylation in these processes, we determined the genome-wide DNA methylation and gene expression profiles of CD24(+)CD61(+)CD29(hi), CD24(+)CD61(+)CD29(lo), and CD24(+)CD61(-)CD29(lo) cell populations that were previously associated with distinct biological properties at different ages and reproductive stages. We found that pregnancy had the most significant effects on CD24(+)CD61(+)CD29(hi) and CD24(+)CD61(+)CD29(lo) cells, inducing distinct epigenetic states that were maintained through life. Integrated analysis of gene expression, DNA methylation, and histone modification profiles revealed cell-type- and reproductive-stage-specific changes. We identified p27 and TGFβ signaling as key regulators of CD24(+)CD61(+)CD29(lo) cell proliferation, based on their expression patterns and results from mammary gland explant cultures. Our results suggest that relatively minor changes in DNA methylation occur during luminal differentiation compared with the effects of pregnancy on CD24(+)CD61(+)CD29(hi) and CD24(+)CD61(+)CD29(lo) cells.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Sung Jin
authors.initials: SJ
authors.lastname: Huh
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139, USA.
authors.forename: Kendell
authors.initials: K
authors.lastname: Clement
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: David
authors.initials: D
authors.lastname: Jee
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Unit of Immunology and General Pathology, Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Merlini
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Sibgat
authors.initials: S
authors.lastname: Choudhury
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Reo
authors.initials: R
authors.lastname: Maruyama
authors.affiliation: Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Children's Hospital Boston, Boston, MA 02115, USA.
authors.forename: Ronnie
authors.initials: R
authors.lastname: Yoo
authors.affiliation: Department of Cancer Biology and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Chytil
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Boyle
authors.affiliation: Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Children's Hospital Boston, Boston, MA 02115, USA.
authors.forename: Fei Ann
authors.initials: FA
authors.lastname: Ran
authors.affiliation: Department of Cancer Biology and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Harold L
authors.initials: HL
authors.lastname: Moses
authors.affiliation: Departments of Radiation Oncology and Cell Biology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Mary Helen
authors.initials: MH
authors.lastname: Barcellos-Hoff
authors.affiliation: Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Children's Hospital Boston, Boston, MA 02115, USA.
authors.forename: Laurie
authors.initials: L
authors.lastname: Jackson-Grusby
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address: alexander_meissner@harvard.edu.
authors.forename: Alexander
authors.initials: A
authors.lastname: Meissner
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, USA. Electronic address: kornelia_polyak@dfci.harvard.edu.
authors.forename: Kornelia
authors.initials: K
authors.lastname: Polyak
mesh_terms: D000367:Age Factors; D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D016000:Cluster Analysis; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D004742:Enhancer Elements, Genetic; D004789:Enzyme Activation; D044127:Epigenesis, Genetic; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism; D016130:Immunophenotyping; D008321:Mammary Glands, Animal / Q000166:cytology*; D051379:Mice; D018345:Mice, Knockout; D009928:Organ Specificity / Q000235:genetics; D010641:Phenotype; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D012741:Sexual Maturation / Q000235:genetics; D015398:Signal Transduction
chemical_list: D000954:Antigens, Surface; D006657:Histones; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases