title: Histone Demethylase KDM6A Controls the Mammary Luminal Lineage through Enzyme-Independent Mechanisms.
abstract: Establishment of the mammary luminal cell lineage is controlled primarily by hormones and through specific transcription factors (TFs). Previous studies have linked histone methyltransferases to the differentiation of mammary epithelium, thus opening the possibility of biological significance of counteracting demethylases. We have now demonstrated an essential role for the H3K27me3 demethylase KDM6A in generating a balanced alveolar compartment. Deletion of Kdm6a in the mammary luminal cell lineage led to a paucity of luminal cells and an excessive expansion of basal cells, both in vivo and in vitro The inability to form structurally normal ducts and alveoli during pregnancy resulted in lactation failure. Mutant luminal cells did not exhibit their distinctive transcription factor pattern and displayed basal characteristics. The genomic H3K27me3 landscape was unaltered in mutant tissue, and support for a demethylase-independent mechanism came from mice expressing a catalytically inactive KDM6A. Mammary tissue developed normally in these mice. Chromatin immunoprecipitation sequencing (ChIP-seq) experiments demonstrated KDM6A binding to putative enhancers enriched for key mammary TFs and H3K27ac. This study demonstrated for the first time that the mammary luminal lineage relies on KDM6A to ensure a transcription program leading to differentiated alveoli. Failure to fully implement this program results in structurally and functionally impaired mammary tissue.
authors.affiliation: Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Kyung Hyun
authors.initials: KH
authors.lastname: Yoo
authors.affiliation: Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA Department of Nanobiomedical Science and BK21 PLUS NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan, Chungnam, Republic of Korea.
authors.forename: Sumin
authors.initials: S
authors.lastname: Oh
authors.affiliation: Department of Microbiology, Dankook University, Cheonan, Chungnam, Republic of Korea.
authors.forename: Keunsoo
authors.initials: K
authors.lastname: Kang
authors.affiliation: Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Chaochen
authors.initials: C
authors.lastname: Wang
authors.affiliation: Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Gertraud W
authors.initials: GW
authors.lastname: Robinson
authors.affiliation: Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Ge
authors.affiliation: Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA lotharh@mail.nih.gov.
authors.forename: Lothar
authors.initials: L
authors.lastname: Hennighausen
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism; D005260:Female; D055786:Gene Knockout Techniques; D056466:Histone Demethylases / Q000235:genetics* / Q000378:metabolism*; D006657:Histones / Q000235:genetics*; D008321:Mammary Glands, Animal / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D011247:Pregnancy; D017423:Sequence Analysis, RNA / Q000379:methods; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D006657:Histones; D014157:Transcription Factors; D056466:Histone Demethylases; C111778:Utx protein, mouse