Differential cytokine sensitivities of STAT5-dependent enhancers rely on Stat5 autoregulation.
Cytokines utilize the transcription factor STAT5 to control cell-specific genes at a larger scale than universal genes, with a mechanistic explanation yet to be supplied. Genome-wide studies have identified putative STAT5-based mammary-specific and universal enhancers, an opportunity to investigate mechanisms underlying their differential response to cytokines. We have now interrogated the integrity and function of both categories of regulatory elements using biological and genetic approaches. During lactation, STAT5 occupies mammary-specific and universal cytokine-responsive elements. Following lactation, prolactin levels decline and mammary-specific STAT5-dependent enhancers are decommissioned within 24 h, while universal regulatory complexes remain intact. These differential sensitivities are linked to STAT5 concentrations and the mammary-specific Stat5 autoregulatory enhancer. In its absence, mammary-specific enhancers, but not universal elements, fail to be fully established. Upon termination of lactation STAT5 binding to a subset of mammary enhancers is substituted by STAT3. No STAT3 binding was observed at the most sensitive STAT5 enhancers suggesting that upon hormone withdrawal their chromatin becomes inaccessible. Lastly, we demonstrate that the mammary-enriched transcription factors GR, ELF5 and NFIB associate with STAT5 at sites lacking bona fide binding motifs. This study provides, for the first time, molecular insight into the differential sensitivities of mammary-specific and universal cytokine-sensing enhancers.
Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health, Bethesda, MD 20892, USA.|Division of Bioinformatics, Biocenter, Medical University of Innsbruck, 6020 Innsbruck, Austria.
Michaela
M
Willi
Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health, Bethesda, MD 20892, USA.|Department of Life Systems, Sookmyung Women's University, Seoul 140-742, Republic of Korea.
Kyung Hyun
KH
Yoo
Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health, Bethesda, MD 20892, USA.
Chaochen
C
Wang
Division of Bioinformatics, Biocenter, Medical University of Innsbruck, 6020 Innsbruck, Austria.
Zlatko
Z
Trajanoski
Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health, Bethesda, MD 20892, USA lotharh@mail.nih.gov.
Lothar
L
Hennighausen
D000818:Animals; D001665:Binding Sites; D047369:Chromatin Immunoprecipitation; D016207:Cytokines / Q000235:genetics*; D004742:Enhancer Elements, Genetic; D005260:Female; D005786:Gene Expression Regulation; D059014:High-Throughput Nucleotide Sequencing; D006706:Homeostasis; D007774:Lactation / Q000235:genetics; D008321:Mammary Glands, Animal / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism*
D016207:Cytokines; D011965:Receptors, Glucocorticoid; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor
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