title: Histone demethylase jumonji AT-rich interactive domain 1B (JARID1B) controls mammary gland development by regulating key developmental and lineage specification genes.
abstract: The JmjC domain-containing H3K4 histone demethylase jumonji AT-rich interactive domain 1B (JARID1B) (also known as KDM5B and PLU1) is overexpressed in breast cancer and is a potential target for breast cancer treatment. To investigate the in vivo function of JARID1B, we developed Jarid1b(-/-) mice and characterized their phenotypes in detail. Unlike previously reported Jarid1b(-/-) strains, the majority of these Jarid1b(-/-) mice were viable beyond embryonic and neonatal stages. This allowed us to further examine phenotypes associated with the loss of JARID1B in pubertal development and pregnancy. These Jarid1b(-/-) mice exhibited decreased body weight, premature mortality, decreased female fertility, and delayed mammary gland development. Related to these phenotypes, JARID1B loss decreased serum estrogen level and reduced mammary epithelial cell proliferation in early puberty. In mammary epithelial cells, JARID1B loss diminished the expression of key regulators for mammary morphogenesis and luminal lineage specification, including FOXA1 and estrogen receptor α. Mechanistically, JARID1B was required for GATA3 recruitment to the Foxa1 promoter to activate Foxa1 expression. These results indicate that JARID1B positively regulates mammary ductal development through both extrinsic and cell-autonomous mechanisms.
authors.affiliation: From the Department of Pathology, Yale School of Medicine, New Haven, Connecticut 06520.
authors.forename: Mike Ran
authors.initials: MR
authors.lastname: Zou
authors.affiliation: From the Department of Pathology, Yale School of Medicine, New Haven, Connecticut 06520.
authors.forename: Jian
authors.initials: J
authors.lastname: Cao
authors.affiliation: From the Department of Pathology, Yale School of Medicine, New Haven, Connecticut 06520.
authors.forename: Zongzhi
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, and.
authors.forename: Sung Jin
authors.initials: SJ
authors.lastname: Huh
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, and Harvard Stem Cell Institute, Cambridge, Massachusetts 02138.
authors.forename: Kornelia
authors.initials: K
authors.lastname: Polyak
authors.affiliation: From the Department of Pathology, Yale School of Medicine, New Haven, Connecticut 06520, qin.yan@yale.edu.
authors.forename: Qin
authors.initials: Q
authors.lastname: Yan
mesh_terms: D000818:Animals; D002460:Cell Line; D019070:Cell Lineage / Q000502:physiology*; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics / Q000378:metabolism; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D008321:Mammary Glands, Animal / Q000166:cytology / Q000196:embryology*; D051379:Mice; D018345:Mice, Knockout; D038081:Organogenesis / Q000502:physiology*; D011247:Pregnancy
chemical_list: D004268:DNA-Binding Proteins; C496500:Foxa1 protein, mouse; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D051541:Hepatocyte Nuclear Factor 3-alpha; D056484:Jumonji Domain-Containing Histone Demethylases; C485614:Kdm5b protein, mouse
keywords: Breast Cancer; Epigenetics; Estrogen; FOXA1; GATA3; Histone Methylation; KDM5B; Luminal Lineage; Mammary Gland Development; Mouse Genetics