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STAT5-Driven Enhancers Tightly Control Temporal Expression of Mammary-Specific Genes

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Abstract

The de novo formation of milk-secreting mammary epithelium during pregnancy is regulated by prolactin through activation of the transcription factor STAT5, which stimulates the expression of several hundred mammary-specific genes. In addition to its key role in activating gene expression in mammary tissue, STAT5, which is ubiquitously expressed in most cell types, implements T cell-specific programs controlled by interleukins. However, the mechanisms by which STAT5 controls cell-specific genetic programs activated by distinct cytokines remain relatively unknown. Integration of data from genome-wide surveys of chromatin markers and transcription factor binding at regulatory elements may shed light on the mechanisms that drive cell-specific programs. Here, we have illustrated how STAT5 controls cell-specific gene expression through its concentration and an auto-regulatory enhancer supporting its high levels in mammary tissue. The unique genomic features of STAT5-driven enhancers or super-enhancers that regulate mammary-specific genes and their dynamic remodeling in response to pregnancy hormone levels are described. We have further provided biological evidence supporting the in vivo function of a STAT5-driven super-enhancer with the aid of CRISPR/Cas9 genome editing. Finally, we discuss how the functions of mammary-specific super-enhancers are confined by the zinc finger protein, CTCF, to allow exclusive activation of mammary-specific genes without affecting common neighboring genes. This review comprehensively summarizes the molecular pathways underlying differential control of cell-specific gene sets by STAT5 and provides novel insights into STAT5-dependent mammary physiology.

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Acknowledgements

This work was supported by grants from Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (S2017R1C1B2002806, S201803S00103) and the IRP of NIDDK/NIH.

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Authors and Affiliations

  1. Department of Biomedical Science and Engineering, Konkuk University, Seoul, 05029, Republic of Korea

    Ha Youn Shin

  2. Laboratory of Genetics and Physiology, National Institutes of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA

    Lothar Hennighausen

  3. BK21 PLUS Project, Sookmyung Women’s University, Seoul, 04310, Republic of Korea

    Lothar Hennighausen

  4. Department of Biological Sciences, Sookmyung Women’s University, Seoul, 04310, Republic of Korea

    Kyung Hyun Yoo

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Shin, H.Y., Hennighausen, L. & Yoo, K.H. STAT5-Driven Enhancers Tightly Control Temporal Expression of Mammary-Specific Genes. J Mammary Gland Biol Neoplasia 24, 61–71 (2019). https://doi.org/10.1007/s10911-018-9418-y

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