title: Global changes in the mammary epigenome are induced by hormonal cues and coordinated by Ezh2.
abstract: The mammary epithelium is a dynamic, highly hormone-responsive tissue. To explore chromatin modifications underlying its lineage specification and hormone responsiveness, we determined genome-wide histone methylation profiles of mammary epithelial subpopulations in different states. The marked differences in H3K27 trimethylation between subpopulations in the adult gland suggest that epithelial cell-fate decisions are orchestrated by polycomb-complex-mediated repression. Remarkably, the mammary epigenome underwent highly specific changes in different hormonal contexts, with a profound change being observed in the global H3K27me3 map of luminal cells during pregnancy. We therefore examined the role of the key H3K27 methyltransferase Ezh2 in mammary physiology. Its expression and phosphorylation coincided with H3K27me3 modifications and peaked during pregnancy, driven in part by progesterone. Targeted deletion of Ezh2 impaired alveologenesis during pregnancy, preventing lactation, and drastically reduced stem/progenitor cell numbers. Taken together, these findings reveal that Ezh2 couples hormonal stimuli to epigenetic changes that underpin progenitor activity, lineage specificity, and alveolar expansion in the mammary gland.
authors: ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville VIC 3052, Australia.
authors: Bhupinder
authors: B
authors: Pal
authors: Toula
authors: T
authors: Bouras
authors: Wei
authors: W
authors: Shi
authors: François
authors: F
authors: Vaillant
authors: Julie M
authors: JM
authors: Sheridan
authors: Naiyang
authors: N
authors: Fu
authors: Kelsey
authors: K
authors: Breslin
authors: Kun
authors: K
authors: Jiang
authors: Matthew E
authors: ME
authors: Ritchie
authors: Matthew
authors: M
authors: Young
authors: Geoffrey J
authors: GJ
authors: Lindeman
authors: Gordon K
authors: GK
authors: Smyth
authors: Jane E
authors: JE
authors: Visvader
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000166:cytology / Q000378:metabolism*; D008745:Methylation; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism*; D063146:Polycomb-Group Proteins / Q000378:metabolism; D011247:Pregnancy; D011374:Progesterone / Q000494:pharmacology; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism
chemical_list: D002843:Chromatin; D006657:Histones; D063146:Polycomb-Group Proteins; D011374:Progesterone; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D063151:Polycomb Repressive Complex 2