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Cell-specific and shared regulatory elements control a multigene locus active in mammary and salivary glands

Author

Listed:
  • Hye Kyung Lee

    (National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health)

  • Michaela Willi

    (National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health)

  • Chengyu Liu

    (Transgenic Core, National Heart, Lung, and Blood Institute, US National Institutes of Health)

  • Lothar Hennighausen

    (National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health)

Abstract

Regulation of high-density loci harboring genes with different cell-specificities remains a puzzle. Here we investigate a locus that evolved through gene duplication and contains eight genes and 20 candidate regulatory elements, including one super-enhancer. Casein genes (Csn1s1, Csn2, Csn1s2a, Csn1s2b, Csn3) are expressed in mammary glands, induced 10,000-fold during pregnancy and account for 50% of mRNAs during lactation, Prr27 and Fdcsp are salivary-specific and Odam has dual specificity. We probed the function of 12 candidate regulatory elements, individually and in combination, in the mouse genome. The super-enhancer is essential for the expression of Csn3, Csn1s2b, Odam and Fdcsp but largely dispensable for Csn1s1, Csn2 and Csn1s2a. Csn3 activation also requires its own local enhancer. Synergism between local enhancers and cytokine-responsive promoter elements facilitates activation of Csn2 during pregnancy. Our work identifies the regulatory complexity of a multigene locus with an ancestral super-enhancer active in mammary and salivary tissue and local enhancers and promoter elements unique to mammary tissue.

Suggested Citation

  • Hye Kyung Lee & Michaela Willi & Chengyu Liu & Lothar Hennighausen, 2023. "Cell-specific and shared regulatory elements control a multigene locus active in mammary and salivary glands," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40712-0
    DOI: 10.1038/s41467-023-40712-0
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    References listed on IDEAS

    as
    1. Hye Kyung Lee & Michaela Willi & Tyler Kuhns & Chengyu Liu & Lothar Hennighausen, 2021. "Redundant and non-redundant cytokine-activated enhancers control Csn1s2b expression in the lactating mouse mammary gland," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    2. Francesco N. Carelli & Angélica Liechti & Jean Halbert & Maria Warnefors & Henrik Kaessmann, 2018. "Repurposing of promoters and enhancers during mammalian evolution," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    3. Tian-Tian Liu & Sunkyung Kim & Pritesh Desai & Do-Hyun Kim & Xiao Huang & Stephen T. Ferris & Renee Wu & Feiya Ou & Takeshi Egawa & Steven J. Van Dyken & Michael S. Diamond & Peter F. Johnson & Masato, 2022. "Ablation of cDC2 development by triple mutations within the Zeb2 enhancer," Nature, Nature, vol. 607(7917), pages 142-148, July.
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    5. Ha Youn Shin & Chaochen Wang & Hye Kyung Lee & Kyung Hyun Yoo & Xianke Zeng & Tyler Kuhns & Chul Min Yang & Teresa Mohr & Chengyu Liu & Lothar Hennighausen, 2017. "CRISPR/Cas9 targeting events cause complex deletions and insertions at 17 sites in the mouse genome," Nature Communications, Nature, vol. 8(1), pages 1-10, August.
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