Different dynamics of gene expression are observed during cell differentiation. In T cells, genes that are turned on early or turned off and stay off have been thoroughly studied. However, genes that are initially turned off but then turned on again after stimulation has ceased have not been defined; they are obviously important, especially in the context of acute versus chronic inflammation. Using the Th1/Th2 differentiation paradigm, we found that the Cxxc1 subunit of the Trithorax complex directs transcription of genes initially down-regulated by TCR stimulation but up-regulated again in a later phase. The late up-regulation of these genes was impaired either by prolonged TCR stimulation or Cxxc1 deficiency, which led to decreased expression of Trib3 and Klf2 in Th1 and Th2 cells, respectively. Loss of Cxxc1 resulted in enhanced pathogenicity in allergic airway inflammation in vivo. Thus, Cxxc1 plays essential roles in the establishment of a proper CD4+ T cell immune system via epigenetic control of a specific set of genes.
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January 12 2021
The Cxxc1 subunit of the Trithorax complex directs epigenetic licensing of CD4+ T cell differentiation
Masahiro Kiuchi,
Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Department of Immunology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan
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Atsushi Onodera,
Conceptualization, Formal analysis, Funding acquisition, Investigation, Writing - original draft, Writing - review & editing
1
Department of Immunology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan
2
Institute for Global Prominent Research, Chiba University, Chuo-ku, Chiba, Japan
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Kota Kokubo,
Kota Kokubo
Project administration, Validation, Visualization, Writing - review & editing
1
Department of Immunology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan
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Tomomi Ichikawa,
Tomomi Ichikawa
Formal analysis, Methodology, Software, Visualization
1
Department of Immunology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan
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Yuki Morimoto,
Yuki Morimoto
Investigation, Writing - review & editing
1
Department of Immunology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan
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Eiryo Kawakami,
Eiryo Kawakami
Formal analysis, Methodology, Software
3
Artificial Intelligence Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan
4
Medical Sciences Innovation Hub Program, RIKEN, Yokohama, Kanagawa, Japan
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Naoya Takayama,
Naoya Takayama
Methodology
5
Department of Regenerative Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan
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Koji Eto,
Koji Eto
Formal analysis, Validation
5
Department of Regenerative Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan
6
Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
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Haruhiko Koseki,
Haruhiko Koseki
Conceptualization, Project administration, Supervision, Writing - original draft
7
Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan
8
Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
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Kiyoshi Hirahara,
Kiyoshi Hirahara
Conceptualization, Funding acquisition, Investigation, Project administration, Supervision, Writing - review & editing
1
Department of Immunology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan
9
AMED-PRIME, Japan Agency for Medical Research and Development, Chiba, Japan
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Toshinori Nakayama
Conceptualization, Data curation, Funding acquisition, Project administration, Supervision, Writing - review & editing
1
Department of Immunology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan
10
Japan Agency for Medical Research and Development–Core Research for Evolutional Medical Science and Technology (AMED-CREST), Chiba, Japan
Correspondence to Toshinori Nakayama: tnakayama@faculty.chiba-u.jp
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Masahiro Kiuchi
Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Department of Immunology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan
Atsushi Onodera
Conceptualization, Formal analysis, Funding acquisition, Investigation, Writing - original draft, Writing - review & editing
1
Department of Immunology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan
2
Institute for Global Prominent Research, Chiba University, Chuo-ku, Chiba, Japan
Kota Kokubo
Project administration, Validation, Visualization, Writing - review & editing
1
Department of Immunology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan
Tomomi Ichikawa
Formal analysis, Methodology, Software, Visualization
1
Department of Immunology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan
Yuki Morimoto
Investigation, Writing - review & editing
1
Department of Immunology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan
Eiryo Kawakami
Formal analysis, Methodology, Software
3
Artificial Intelligence Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan
4
Medical Sciences Innovation Hub Program, RIKEN, Yokohama, Kanagawa, Japan
Naoya Takayama
Methodology
5
Department of Regenerative Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan
Koji Eto
Formal analysis, Validation
5
Department of Regenerative Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan
6
Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
Haruhiko Koseki
Conceptualization, Project administration, Supervision, Writing - original draft
7
Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan
8
Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
Kiyoshi Hirahara
Conceptualization, Funding acquisition, Investigation, Project administration, Supervision, Writing - review & editing
1
Department of Immunology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan
9
AMED-PRIME, Japan Agency for Medical Research and Development, Chiba, Japan
Toshinori Nakayama
Conceptualization, Data curation, Funding acquisition, Project administration, Supervision, Writing - review & editing
1
Department of Immunology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan
10
Japan Agency for Medical Research and Development–Core Research for Evolutional Medical Science and Technology (AMED-CREST), Chiba, Japan
Correspondence to Toshinori Nakayama: tnakayama@faculty.chiba-u.jp
*
M. Kiuchi and A. Onodera contributed equally to this paper.
Received:
August 07 2020
Revision Received:
November 16 2020
Accepted:
November 19 2020
Online Issn: 1540-9538
Print Issn: 0022-1007
Funding:
Japan Agency for Medical Research and Development
(JP20ek0410060, JP19ek0410045)
Ministry of Education, Culture, Sports, Science and Technology
((S) 26221305, JP19H05650, (B) 20H03685, (C) 17K08876, 18K07164, 19K16683)
Mochida Memorial Foundation for Medical and Pharmaceutical Research
(NO AWARD)
MSD Life Science Foundation, Public Interest Incorporated Foundation
(NO AWARD)
Naito Foundation
(NO AWARD)
Takeda Science Foundation
(NO AWARD)
© 2021 Kiuchi et al.
2021
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Exp Med (2021) 218 (4): e20201690.
Article history
Received:
August 07 2020
Revision Received:
November 16 2020
Accepted:
November 19 2020
Citation
Masahiro Kiuchi, Atsushi Onodera, Kota Kokubo, Tomomi Ichikawa, Yuki Morimoto, Eiryo Kawakami, Naoya Takayama, Koji Eto, Haruhiko Koseki, Kiyoshi Hirahara, Toshinori Nakayama; The Cxxc1 subunit of the Trithorax complex directs epigenetic licensing of CD4+ T cell differentiation. J Exp Med 5 April 2021; 218 (4): e20201690. doi: https://doi.org/10.1084/jem.20201690
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