Age- and pregnancy-associated DNA methylation changes in mammary epithelial cells.

Huh SJ, Clement K, Jee D, Merlini A, Choudhury S, Maruyama R, Yoo R, Chytil A, Boyle P, Ran FA, Moses HL, Barcellos-Hoff MH, Jackson-Grusby L, Meissner A, Polyak K
Stem Cell Reports. 2015 4 (2): 297-311

PMID: 25619437 · PMCID: PMC4325231 · DOI:10.1016/j.stemcr.2014.12.009

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.

Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

MeSH Terms (26)

Age Factors Animals Antigens, Surface Cell Differentiation Cluster Analysis DNA (Cytosine-5-)-Methyltransferase 1 DNA (Cytosine-5-)-Methyltransferases DNA Methylation Enhancer Elements, Genetic Enzyme Activation Epigenesis, Genetic Epithelial Cells Female Gene Expression Profiling Gene Expression Regulation Histones Immunophenotyping Mammary Glands, Animal Mice Mice, Knockout Organ Specificity Phenotype Pregnancy Promoter Regions, Genetic Sexual Maturation Signal Transduction

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