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The cis-regulation of Aire Expression.

LaFlam, Taylor Nicholas.

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The cis-regulation of Aire Expression.

Record Type:	Electronic resources : Monograph/item
Title/Author:	The cis-regulation of Aire Expression./
Author:	LaFlam, Taylor Nicholas.
Description:	169 p.
Notes:	Source: Dissertation Abstracts International, Volume: 76-11(E), Section: B.
Contained By:	Dissertation Abstracts International76-11B(E).
Subject:	Immunology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3712567
ISBN:	9781321894868

The cis-regulation of Aire Expression.
LaFlam, Taylor Nicholas.

The cis-regulation of Aire Expression. - 169 p.

Source: Dissertation Abstracts International, Volume: 76-11(E), Section: B.

Thesis (Ph.D.)--University of California, San Francisco, 2015.

Immune self-tolerance, the absence of an immune response against the body, is an active process involving several complementary mechanisms. The autoimmune regulator gene (Aire) plays a critical role in this process by inducing the expression of a diverse set of tissue-specific antigens (TSAs) in medullary thymic epithelial cells (mTECs). These TSAs are presented and help eliminate or control self-reactive thymocytes. The expression of Aire is highly restricted, occurring in adults only in mTECs and extrathymic Aire-expressing cells (eTACs), which are found in secondary lymphoid tissues. How this specific pattern of expression is achieved has remained unclear. Although RANK and non-canonical NF-kappaB signaling are known to be important for the development and maintenance of Aire-expressing mTECs, the cis-regulation of Aire is poorly understood. We aimed to discover distal cis -regulatory elements that control Aire. Here, we identify a conserved DNA element that is essential for Aire expression. We find enrichment of enhancer-associated histone marks near this element, which we call ACNS1 and show to be NF-kappaB-responsive. We demonstrate that a 4.3-kb region, which includes ACNS1 and the Aire promoter, is sufficient to recapitulate the cell-type specificity of Aire expression. We show that ACNS1 is essential for Aire expression in mTECs and eTACs in vivo and is required to prevent spontaneous autoimmunity. We also observe that Aire and Dnmt3l are co-expressed and that ACNS1 is necessary for thymic Dnmt3l expression. Finally, we present preliminary evidence for additional Aire cis-regulatory elements. Together, these findings further our understanding of the control of immune tolerance and may lead to improvements in the diagnosis and treatment of autoimmune disease.

ISBN: 9781321894868Subjects--Topical Terms:

611031
Immunology.

The cis-regulation of Aire Expression.
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