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Identification of an Intronic Regulatory Element Necessary for Tissue-Specific Expression of Foxn1 in Thymic Epithelial Cells

  1. Author:
    Larsen, Brian M [ORCID]
    Cowan, Jennifer E
    Wang, Yueqiang [ORCID]
    Tanaka, Yu
    Zhao, Yongge [ORCID]
    Voisin, Benjamin
    Constantinides, Michael G [ORCID]
    Nagao, Keisuke [ORCID]
    Belkaid, Yasmine
    Awasthi,Roackie
    Takahama, Yousuke
    Bhandoola, Avinash [ORCID]

  2. Author Address

    Laboratory of Genome Integrity, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892., Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892., Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892., Metaorganism Immunity Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and., Laboratory Animal Sciences Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, National Institutes of Health, Frederick, MD 21701., Laboratory of Genome Integrity, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; avinash.bhandoola@nih.gov.,
    1. Year: 2019
    2. Date: AUG 1
    3. Epub Date: 2019 06 26
  2. Journal: Journal of immunology (Baltimore, Md. : 1950)
    1. 203
    2. 3
    3. Pages: 686-695
  4. Type of Article: Article
  5. ISSN: 0022-1767
  1. Abstract:

    The thymus is critical for the establishment of the adaptive immune system and the development of a diverse T cell repertoire. T cell development depends upon cell-cell interactions with epithelial cells in the thymus. The thymus is composed of two different types of epithelial cells: cortical and medullary epithelial cells. Both of these express and critically depend on the transcription factor Foxn1Foxn1 is also expressed in the hair follicle, and disruption of Foxn1 function in mice results in severe thymic developmental defects and the hairless (nude) phenotype. Despite its importance, little is known about the direct regulation of Foxn1 expression. In this study, we identify a cis-regulatory element (RE) critical for expression of Foxn1 in mouse thymic epithelial cells but dispensable for expression in hair follicles. Analysis of chromatin accessibility, histone modifications, and sequence conservation identified regions within the first intron of Foxn1 that possessed the characteristics of REs. Systematic knockout of candidate regions lead us to identify a 1.6 kb region that, when deleted, results in a near total disruption of thymus development. Interestingly, Foxn1 expression and function in the hair follicle were unaffected. RNA fluorescent in situ hybridization showed a near complete loss of Foxn1 mRNA expression in the embryonic thymic bud. Our studies have identified a genomic RE with thymic-specific control of Foxn1 gene expression.

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External Sources

  1. View Full Text
  2. DOI: 10.4049/jimmunol.1801540
  3. PMID: 31243087
  4. View record in Web of Science®
  5. WOS: 000476650600011
  6. PII : jimmunol.1801540

Library Notes

  1. Fiscal Year: FY2018-2019
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