title: An autoregulatory enhancer controls mammary-specific STAT5 functions.
abstract: Signal Transducers and Activators of Transcription (STATs) are principal transcription factors downstream of cytokine receptors. Although STAT5A is expressed in most tissues it remains to be understood why its premier, non-redundant functions are restricted to prolactin-induced mammary gland development and function. We report that the ubiquitously expressed Stat5a/b locus is subject to additional lineage-specific transcriptional control in mammary epithelium. Genome-wide surveys of epigenetic status and transcription factor occupancy uncovered a putative mammary-specific enhancer within the intergenic sequences separating the two Stat5 genes. This region exhibited several hallmarks of genomic enhancers, including DNaseI hypersensitivity, H3K27 acetylation and binding by GR, NFIB, ELF5 and MED1. Mammary-specific STAT5 binding was obtained at two canonical STAT5 binding motifs. CRISPR/Cas9-mediated genome editing was used to delete these sites in mice and determine their biological function. Mutant animals exhibited an 80% reduction of Stat5 levels in mammary epithelium and a concomitant reduction of STAT5-dependent gene expression. Transcriptome analysis identified a class of mammary-restricted genes that was particularly dependent on high STAT5 levels as a result of the intergenic enhancer. Taken together, the mammary-specific enhancer enables a positive feedback circuit that contributes to the remarkable abundance of STAT5 and, in turn, to the efficacy of STAT5-dependent mammary physiology.
authors.affiliation: Laboratory of Genetics and Physiology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Gil
authors.initials: G
authors.lastname: Metser
authors.affiliation: Laboratory of Genetics and Physiology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Ha Youn
authors.initials: HY
authors.lastname: Shin
authors.affiliation: Laboratory of Genetics and Physiology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Chaochen
authors.initials: C
authors.lastname: Wang
authors.affiliation: Laboratory of Genetics and Physiology, National Institute 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 Institute 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: Sumin
authors.initials: S
authors.lastname: Oh
authors.affiliation: Molecular Immunology and Inflammation Branch, NIAMS, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Alejandro V
authors.initials: AV
authors.lastname: Villarino
authors.affiliation: Molecular Immunology and Inflammation Branch, NIAMS, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: O'Shea
authors.affiliation: 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 Institute 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; D001483:Base Sequence; D064112:Clustered Regularly Interspaced Short Palindromic Repeats / Q000235:genetics; D004247:DNA; D004742:Enhancer Elements, Genetic; D005260:Female; D006801:Humans; D042361:Mammary Glands, Human / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000502:physiology*
chemical_list: D050799:STAT5 Transcription Factor; D004247:DNA