Transcriptional programs that control expression of the autoimmune regulator gene Aire

Yonatan Herzig; Shir Nevo; Chamutal Bornstein; Miriam R. Brezis; Sharon Ben-Hur; Aya Shkedy; Michal Eisenberg-Bord; Ben Levi; Michael Delacher; Yael Goldfarb; Eyal David; Leehee Weinberger; Sergey Viukov; Shifra Ben-Dor; Matthieu Giraud; Jacob H. Hanna; Achim Breiling; Frank Lyko; Ido Amit; Markus Feuerer; Jakub Abramson

doi:10.1038/ni.3638

Transcriptional programs that control expression of the autoimmune regulator gene Aire

Yonatan Herzig, Shir Nevo, Chamutal Bornstein, Miriam R. Brezis, Sharon Ben-Hur, Aya Shkedy, Michal Eisenberg-Bord, Ben Levi, Michael Delacher, Yael Goldfarb, Eyal David, Leehee Weinberger, Sergey Viukov, Shifra Ben-Dor, Matthieu Giraud, Jacob H. Hanna, Achim Breiling, Frank Lyko, Ido Amit, Markus FeuererJakub Abramson

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41 Citations (Scopus)

Abstract

Aire is a transcriptional regulator that induces promiscuous expression of thousands of genes encoding tissue-restricted antigens (TRAs) in medullary thymic epithelial cells (mTECs). While the target genes of Aire are well characterized, the transcriptional programs that regulate its own expression have remained elusive. Here we comprehensively analyzed both cis-Acting and trans-Acting regulatory mechanisms and found that the Aire locus was insulated by the global chromatin organizer CTCF and was hypermethylated in cells and tissues that did not express Aire. In mTECs, however, Aire expression was facilitated by concurrent eviction of CTCF, specific demethylation of exon 2 and the proximal promoter, and the coordinated action of several transcription activators, including Irf4, Irf8, Tbx21, Tcf7 and Ctcfl, which acted on mTEC-specific accessible regions in the Aire locus.

Original language	English
Pages (from-to)	161-172
Number of pages	12
Journal	Nature Immunology
Volume	18
Issue number	2
DOIs	https://doi.org/10.1038/ni.3638
Publication status	Published - 1 Feb 2017

Bibliographical note

We thank M. Anderson (University of California at San Francisco) for Aire-Igrp-GFP mice; D. Graf (University of Zurich) for B6.Foxn1-Cre mice (obtained with the consent of N. Manley (University of Georgia)); H. Clevers (Hubrecht Institute) for Tcf7−/− mice; and Y. Peleg, G. Yona and V. Krupalnik for experimental expertise and help. Supported by the Israel Science Foundation (1825/10 and 1376/13), the Sy Syms Foundation, the Dr. Celia Zwillenberg-Fridman and Dr. Lutz Fridman Career Development Chair (J.A.), the Weizmann-German Cancer Research Center PhD fellowship program (Y.H., M.D., J.A., M.F.), the German Cancer Research Center–Israeli Ministry of Science and Technology foundation for German-Israeli co-operation (2431 to J.A. and M.F.), the Agence Nationale de Recherche (2011-CHEX-001-R12004KK to M.Gi.) and the European Federation of Immunological Societies fellowship program (M.R.B.).

Publisher Copyright:
© 2017 nature America, Inc., part of Springer Nature. All rights reserved.

All Science Journal Classification (ASJC) codes

Immunology and Allergy
Immunology

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10.1038/ni.3638

Cite this

Herzig, Y., Nevo, S., Bornstein, C., Brezis, M. R., Ben-Hur, S., Shkedy, A., Eisenberg-Bord, M., Levi, B., Delacher, M., Goldfarb, Y., David, E., Weinberger, L., Viukov, S., Ben-Dor, S., Giraud, M., Hanna, J. H., Breiling, A., Lyko, F., Amit, I., ... Abramson, J. (2017). Transcriptional programs that control expression of the autoimmune regulator gene Aire. Nature Immunology, 18(2), 161-172. https://doi.org/10.1038/ni.3638

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title = "Transcriptional programs that control expression of the autoimmune regulator gene Aire",

abstract = "Aire is a transcriptional regulator that induces promiscuous expression of thousands of genes encoding tissue-restricted antigens (TRAs) in medullary thymic epithelial cells (mTECs). While the target genes of Aire are well characterized, the transcriptional programs that regulate its own expression have remained elusive. Here we comprehensively analyzed both cis-Acting and trans-Acting regulatory mechanisms and found that the Aire locus was insulated by the global chromatin organizer CTCF and was hypermethylated in cells and tissues that did not express Aire. In mTECs, however, Aire expression was facilitated by concurrent eviction of CTCF, specific demethylation of exon 2 and the proximal promoter, and the coordinated action of several transcription activators, including Irf4, Irf8, Tbx21, Tcf7 and Ctcfl, which acted on mTEC-specific accessible regions in the Aire locus.",

author = "Yonatan Herzig and Shir Nevo and Chamutal Bornstein and Brezis, {Miriam R.} and Sharon Ben-Hur and Aya Shkedy and Michal Eisenberg-Bord and Ben Levi and Michael Delacher and Yael Goldfarb and Eyal David and Leehee Weinberger and Sergey Viukov and Shifra Ben-Dor and Matthieu Giraud and Hanna, {Jacob H.} and Achim Breiling and Frank Lyko and Ido Amit and Markus Feuerer and Jakub Abramson",

note = "We thank M. Anderson (University of California at San Francisco) for Aire-Igrp-GFP mice; D. Graf (University of Zurich) for B6.Foxn1-Cre mice (obtained with the consent of N. Manley (University of Georgia)); H. Clevers (Hubrecht Institute) for Tcf7−/− mice; and Y. Peleg, G. Yona and V. Krupalnik for experimental expertise and help. Supported by the Israel Science Foundation (1825/10 and 1376/13), the Sy Syms Foundation, the Dr. Celia Zwillenberg-Fridman and Dr. Lutz Fridman Career Development Chair (J.A.), the Weizmann-German Cancer Research Center PhD fellowship program (Y.H., M.D., J.A., M.F.), the German Cancer Research Center–Israeli Ministry of Science and Technology foundation for German-Israeli co-operation (2431 to J.A. and M.F.), the Agence Nationale de Recherche (2011-CHEX-001-R12004KK to M.Gi.) and the European Federation of Immunological Societies fellowship program (M.R.B.). Publisher Copyright: {\textcopyright} 2017 nature America, Inc., part of Springer Nature. All rights reserved.",

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doi = "10.1038/ni.3638",

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Herzig, Y, Nevo, S, Bornstein, C, Brezis, MR, Ben-Hur, S, Shkedy, A, Eisenberg-Bord, M, Levi, B, Delacher, M, Goldfarb, Y , David, E, Weinberger, L, Viukov, S, Ben-Dor, S, Giraud, M, Hanna, JH, Breiling, A, Lyko, F, Amit, I, Feuerer, M & Abramson, J 2017, 'Transcriptional programs that control expression of the autoimmune regulator gene Aire', Nature Immunology, vol. 18, no. 2, pp. 161-172. https://doi.org/10.1038/ni.3638

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T1 - Transcriptional programs that control expression of the autoimmune regulator gene Aire

AU - Herzig, Yonatan

AU - Nevo, Shir

AU - Bornstein, Chamutal

AU - Brezis, Miriam R.

AU - Ben-Hur, Sharon

AU - Shkedy, Aya

AU - Eisenberg-Bord, Michal

AU - Levi, Ben

AU - Delacher, Michael

AU - Goldfarb, Yael

AU - David, Eyal

AU - Weinberger, Leehee

AU - Viukov, Sergey

AU - Ben-Dor, Shifra

AU - Giraud, Matthieu

AU - Hanna, Jacob H.

AU - Breiling, Achim

AU - Lyko, Frank

AU - Amit, Ido

AU - Feuerer, Markus

AU - Abramson, Jakub

N1 - We thank M. Anderson (University of California at San Francisco) for Aire-Igrp-GFP mice; D. Graf (University of Zurich) for B6.Foxn1-Cre mice (obtained with the consent of N. Manley (University of Georgia)); H. Clevers (Hubrecht Institute) for Tcf7−/− mice; and Y. Peleg, G. Yona and V. Krupalnik for experimental expertise and help. Supported by the Israel Science Foundation (1825/10 and 1376/13), the Sy Syms Foundation, the Dr. Celia Zwillenberg-Fridman and Dr. Lutz Fridman Career Development Chair (J.A.), the Weizmann-German Cancer Research Center PhD fellowship program (Y.H., M.D., J.A., M.F.), the German Cancer Research Center–Israeli Ministry of Science and Technology foundation for German-Israeli co-operation (2431 to J.A. and M.F.), the Agence Nationale de Recherche (2011-CHEX-001-R12004KK to M.Gi.) and the European Federation of Immunological Societies fellowship program (M.R.B.). Publisher Copyright: © 2017 nature America, Inc., part of Springer Nature. All rights reserved.

PY - 2017/2/1

Y1 - 2017/2/1

N2 - Aire is a transcriptional regulator that induces promiscuous expression of thousands of genes encoding tissue-restricted antigens (TRAs) in medullary thymic epithelial cells (mTECs). While the target genes of Aire are well characterized, the transcriptional programs that regulate its own expression have remained elusive. Here we comprehensively analyzed both cis-Acting and trans-Acting regulatory mechanisms and found that the Aire locus was insulated by the global chromatin organizer CTCF and was hypermethylated in cells and tissues that did not express Aire. In mTECs, however, Aire expression was facilitated by concurrent eviction of CTCF, specific demethylation of exon 2 and the proximal promoter, and the coordinated action of several transcription activators, including Irf4, Irf8, Tbx21, Tcf7 and Ctcfl, which acted on mTEC-specific accessible regions in the Aire locus.

AB - Aire is a transcriptional regulator that induces promiscuous expression of thousands of genes encoding tissue-restricted antigens (TRAs) in medullary thymic epithelial cells (mTECs). While the target genes of Aire are well characterized, the transcriptional programs that regulate its own expression have remained elusive. Here we comprehensively analyzed both cis-Acting and trans-Acting regulatory mechanisms and found that the Aire locus was insulated by the global chromatin organizer CTCF and was hypermethylated in cells and tissues that did not express Aire. In mTECs, however, Aire expression was facilitated by concurrent eviction of CTCF, specific demethylation of exon 2 and the proximal promoter, and the coordinated action of several transcription activators, including Irf4, Irf8, Tbx21, Tcf7 and Ctcfl, which acted on mTEC-specific accessible regions in the Aire locus.

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DO - 10.1038/ni.3638

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JF - Nature Immunology

IS - 2

ER -

Transcriptional programs that control expression of the autoimmune regulator gene Aire

Abstract

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