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Identification of a novel cis-regulatory element essential for immune tolerance.

The Journal of experimental medicine | 2015

Thymic central tolerance is essential to preventing autoimmunity. In medullary thymic epithelial cells (mTECs), the Autoimmune regulator (Aire) gene plays an essential role in this process by driving the expression of a diverse set of tissue-specific antigens (TSAs), which are presented and help tolerize self-reactive thymocytes. Interestingly, Aire has a highly tissue-restricted pattern of expression, with only mTECs and peripheral extrathymic Aire-expressing cells (eTACs) known to express detectable levels in adults. Despite this high level of tissue specificity, the cis-regulatory elements that control Aire expression have remained obscure. Here, we identify a highly conserved noncoding DNA element that is essential for Aire expression. This element shows enrichment of enhancer-associated histone marks in mTECs and also has characteristics of being an NF-κB-responsive element. Finally, we find that this element is essential for Aire expression in vivo and necessary to prevent spontaneous autoimmunity, reflecting the importance of this regulatory DNA element in promoting immune tolerance.

Pubmed ID: 26527800 RIS Download

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None found

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Associated grants

  • Agency: NIH HHS, United States
    Id: S10 OD016262
  • Agency: NIDDK NIH HHS, United States
    Id: P30 DK063720
  • Agency: NIAID NIH HHS, United States
    Id: T32 AI007334
  • Agency: NIDDK NIH HHS, United States
    Id: F30 DK100098
  • Agency: NIGMS NIH HHS, United States
    Id: T32 GM007618
  • Agency: NIDDK NIH HHS, United States
    Id: R01 DK101622
  • Agency: NHLBI NIH HHS, United States
    Id: R01 HL114093
  • Agency: NICHD NIH HHS, United States
    Id: K12 HD072222
  • Agency: NIAID NIH HHS, United States
    Id: R01 AI097457

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