Identification of a novel cis-regulatory element essential for immune tolerance
Identification of a novel cis-regulatory element essential for immune tolerance
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.
1993-2002
Laflam, Taylor N.
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Seumois, Grégory
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Miller, Corey N.
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Lwin, Wint
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Fasano, Kayla J.
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Waterfield, Michael
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Proekt, Irina
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Vijayanand, Pandurangan
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Anderson, Mark S.
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16 November 2015
Laflam, Taylor N.
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Seumois, Grégory
0be7d3d6-5526-458c-aa5c-cce52410a2ed
Miller, Corey N.
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Lwin, Wint
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Fasano, Kayla J.
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Waterfield, Michael
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Proekt, Irina
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Vijayanand, Pandurangan
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Anderson, Mark S.
be48ded5-417a-4219-a563-f1c7b73c3609
Laflam, Taylor N., Seumois, Grégory, Miller, Corey N., Lwin, Wint, Fasano, Kayla J., Waterfield, Michael, Proekt, Irina, Vijayanand, Pandurangan and Anderson, Mark S.
(2015)
Identification of a novel cis-regulatory element essential for immune tolerance.
The Journal of Experimental Medicine, 212 (12), .
(doi:10.1084/jem.20151069).
Abstract
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.
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Laflam-2015-Identification-of-a-novel-cis-regul
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Accepted/In Press date: 1 October 2015
e-pub ahead of print date: 2 November 2015
Published date: 16 November 2015
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Local EPrints ID: 436481
URI: http://eprints.soton.ac.uk/id/eprint/436481
ISSN: 0022-1007
PURE UUID: e0a7738f-571a-4836-9ac7-6d8bc8b39eac
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Date deposited: 11 Dec 2019 17:30
Last modified: 16 Mar 2024 05:37
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Contributors
Author:
Taylor N. Laflam
Author:
Grégory Seumois
Author:
Corey N. Miller
Author:
Wint Lwin
Author:
Kayla J. Fasano
Author:
Michael Waterfield
Author:
Irina Proekt
Author:
Pandurangan Vijayanand
Author:
Mark S. Anderson
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