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Cell Rep. 2016 Dec 20;17(12):3333-3346. doi: 10.1016/j.celrep.2016.11.079.

Lineage-Specific and Non-specific Cytokine-Sensing Genes Respond Differentially to the Master Regulator STAT5.

Author information

1
Laboratory of Genetics and Physiology, National Institute of Diabetes, Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA.
2
Laboratory of Genetics and Physiology, National Institute of Diabetes, Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA; Division of Bioinformatics, Biocenter, Medical University of Innsbruck, 6020 Innsbruck, Austria.
3
Laboratory of Genetics and Physiology, National Institute of Diabetes, Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA. Electronic address: lotharh@mail.nih.gov.
4
Laboratory of Genetics and Physiology, National Institute of Diabetes, Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA. Electronic address: wangcn@mail.nih.gov.

Abstract

STAT5, a member of the family of signal transducers and activators of transcription, senses cytokines and controls the biology of cell lineages, including mammary, liver, and T cells. Here, we show that STAT5 activates lineage-specific and widely expressed genes through different mechanisms. STAT5 preferentially binds to promoter sequences of cytokine-responsive genes expressed across cell types and to putative enhancers of lineage-specific genes. While chromatin accessibility of STAT5-based enhancers was dependent on cytokine exposure, STAT5-responsive promoters of widely expressed target genes were generally constitutively accessible. While the contribution of STAT5 to enhancers is well established, its role on promoters is poorly understood. To address this, we focused on Socs2, a widely expressed cytokine-sensing gene. Upon deletion of the STAT5 response elements from the Socs2 promoter in mice, cytokine induction was abrogated, while basal activity remained intact. Our data suggest that promoter-bound STAT5 modulates cytokine responses and enhancer-bound STAT5 is mandatory for gene activation.

KEYWORDS:

SOCS2; STAT5; cytokine; enhancer; mammary gland; promoter

PMID:
28009300
PMCID:
PMC5217531
DOI:
10.1016/j.celrep.2016.11.079
[Indexed for MEDLINE]
Free PMC Article

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