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Nucleic Acids Res. 2016 Feb 18;44(3):1052-63. doi: 10.1093/nar/gkv999. Epub 2015 Oct 7.

An autoregulatory enhancer controls mammary-specific STAT5 functions.

Author information

1
Laboratory of Genetics and Physiology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
2
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.
3
Molecular Immunology and Inflammation Branch, NIAMS, National Institutes of Health, Bethesda, MD 20892, USA.
4
Department of Microbiology, Dankook University, Cheonan, Chungnam 330-714, Republic of Korea.
5
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.

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.

PMID:
26446995
PMCID:
PMC4756855
DOI:
10.1093/nar/gkv999
[Indexed for MEDLINE]
Free PMC Article

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