title: Loss of EZH2 results in precocious mammary gland development and activation of STAT5-dependent genes.
abstract: Establishment and differentiation of mammary alveoli during pregnancy are controlled by prolactin through the transcription factors STAT5A and STAT5B (STAT5), which also regulate temporal activation of mammary signature genes. This study addressed the question whether the methyltransferase and transcriptional co-activator EZH2 controls the differentiation clock of mammary epithelium. Ablation of Ezh2 from mammary stem cells resulted in precocious differentiation of alveolar epithelium during pregnancy and the activation of mammary-specific STAT5 target genes. This coincided with enhanced occupancy of these loci by STAT5, EZH1 and RNA Pol II. Limited activation of differentiation-specific genes was observed in mammary epithelium lacking both EZH2 and STAT5, suggesting a modulating but not mandatory role for STAT5. Loss of EZH2 did not result in overt changes in genome-wide and gene-specific H3K27me3 profiles, suggesting compensation through enhanced EZH1 recruitment. Differentiated mammary epithelia did not form in the combined absence of EZH1 and EZH2. Transplantation experiments failed to demonstrate a role for EZH2 in the activity of mammary stem and progenitor cells. In summary, while EZH1 and EZH2 serve redundant functions in the establishment of H3K27me3 marks and the formation of mammary alveoli, the presence of EZH2 is required to control progressive differentiation of milk secreting epithelium during pregnancy.
authors.affiliation: Laboratory of Genetics and Physiology, National Institutes of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Kyung Hyun
authors.initials: KH
authors.lastname: Yoo
authors.affiliation: Laboratory of Genetics and Physiology, National Institutes of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA Department of Nanobiomedical Science and BK21 PLUS NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan, Chungnam 330-714, Republic of Korea.
authors.forename: Sumin
authors.initials: S
authors.lastname: Oh
authors.affiliation: Laboratory of Genetics and Physiology, National Institutes of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA Department of Microbiology, Dankook University, Cheonan, Chungnam 330-714, Republic of Korea.
authors.forename: Keunsoo
authors.initials: K
authors.lastname: Kang
authors.affiliation: Laboratory of Genetics and Physiology, National Institutes of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Tim
authors.initials: T
authors.lastname: Hensel
authors.affiliation: Laboratory of Genetics and Physiology, National Institutes of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Gertraud W
authors.initials: GW
authors.lastname: Robinson
authors.affiliation: Laboratory of Genetics and Physiology, National Institutes of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA lotharh@mail.nih.gov.
authors.forename: Lothar
authors.initials: L
authors.lastname: Hennighausen
mesh_terms: D000818:Animals; D000071221:Enhancer of Zeste Homolog 2 Protein; D004848:Epithelium / Q000378:metabolism; D005260:Female; D042421:Histone Code; D007774:Lactation / Q000235:genetics*; D008321:Mammary Glands, Animal / Q000254:growth & development / Q000378:metabolism*; D008822:Mice, Transgenic; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011247:Pregnancy; D012319:RNA Polymerase II / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D050799:STAT5 Transcription Factor; D000071221:Enhancer of Zeste Homolog 2 Protein; C498408:Ezh1 protein, mouse; C498410:Ezh2 protein, mouse; D063151:Polycomb Repressive Complex 2; D012319:RNA Polymerase II