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MBD2 acts as a repressor to maintain the homeostasis of the Th1 program in type 1 diabetes by regulating the STAT1-IFN-γ axis
The methyl-CpG-binding domain 2 (MBD2) interprets DNA methylome-encoded information through binding to the methylated CpG DNA, by which it regulates target gene expression at the transcriptional level. Although derailed DNA methylation has long been recognized to trigger or promote autoimmune respon...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8738722/ https://www.ncbi.nlm.nih.gov/pubmed/34420035 http://dx.doi.org/10.1038/s41418-021-00852-6 |
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author | Yue, Tiantian Sun, Fei Wang, Faxi Yang, Chunliang Luo, Jiahui Rong, Shanjie Zhou, Haifeng Xiao, Jun Wang, Xiaohui Zhou, Qing Yang, Ping Zhang, Shu Li, Wen Xiong, Fei Yu, Qilin Wang, Cong-Yi |
author_facet | Yue, Tiantian Sun, Fei Wang, Faxi Yang, Chunliang Luo, Jiahui Rong, Shanjie Zhou, Haifeng Xiao, Jun Wang, Xiaohui Zhou, Qing Yang, Ping Zhang, Shu Li, Wen Xiong, Fei Yu, Qilin Wang, Cong-Yi |
author_sort | Yue, Tiantian |
collection | PubMed |
description | The methyl-CpG-binding domain 2 (MBD2) interprets DNA methylome-encoded information through binding to the methylated CpG DNA, by which it regulates target gene expression at the transcriptional level. Although derailed DNA methylation has long been recognized to trigger or promote autoimmune responses in type 1 diabetes (T1D), the exact role of MBD2 in T1D pathogenesis, however, remains poorly defined. Herein, we generated an Mbd2 knockout model in the NOD background and found that Mbd2 deficiency exacerbated the development of spontaneous T1D in NOD mice. Adoptive transfer of Mbd2(−/)(−) CD4 T cells into NOD.scid mice further confirmed the observation. Mechanistically, Th1 stimulation rendered the Stat1 promoter to undergo a DNA methylation turnover featured by the changes of DNA methylation levels or patterns along with the induction of MBD2 expression, which then bound to the methylated CpG DNA within the Stat1 promoter, by which MBD2 maintains the homeostasis of Th1 program to prevent autoimmunity. As a result, ectopic MBD2 expression alleviated CD4 T cell diabetogenicity following their adoptive transfer into NOD.scid mice. Collectively, our data suggest that MBD2 could be a viable target to develop epigenetic-based therapeutics against T1D in clinical settings. |
format | Online Article Text |
id | pubmed-8738722 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-87387222022-01-20 MBD2 acts as a repressor to maintain the homeostasis of the Th1 program in type 1 diabetes by regulating the STAT1-IFN-γ axis Yue, Tiantian Sun, Fei Wang, Faxi Yang, Chunliang Luo, Jiahui Rong, Shanjie Zhou, Haifeng Xiao, Jun Wang, Xiaohui Zhou, Qing Yang, Ping Zhang, Shu Li, Wen Xiong, Fei Yu, Qilin Wang, Cong-Yi Cell Death Differ Article The methyl-CpG-binding domain 2 (MBD2) interprets DNA methylome-encoded information through binding to the methylated CpG DNA, by which it regulates target gene expression at the transcriptional level. Although derailed DNA methylation has long been recognized to trigger or promote autoimmune responses in type 1 diabetes (T1D), the exact role of MBD2 in T1D pathogenesis, however, remains poorly defined. Herein, we generated an Mbd2 knockout model in the NOD background and found that Mbd2 deficiency exacerbated the development of spontaneous T1D in NOD mice. Adoptive transfer of Mbd2(−/)(−) CD4 T cells into NOD.scid mice further confirmed the observation. Mechanistically, Th1 stimulation rendered the Stat1 promoter to undergo a DNA methylation turnover featured by the changes of DNA methylation levels or patterns along with the induction of MBD2 expression, which then bound to the methylated CpG DNA within the Stat1 promoter, by which MBD2 maintains the homeostasis of Th1 program to prevent autoimmunity. As a result, ectopic MBD2 expression alleviated CD4 T cell diabetogenicity following their adoptive transfer into NOD.scid mice. Collectively, our data suggest that MBD2 could be a viable target to develop epigenetic-based therapeutics against T1D in clinical settings. Nature Publishing Group UK 2021-08-21 2022-01 /pmc/articles/PMC8738722/ /pubmed/34420035 http://dx.doi.org/10.1038/s41418-021-00852-6 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Yue, Tiantian Sun, Fei Wang, Faxi Yang, Chunliang Luo, Jiahui Rong, Shanjie Zhou, Haifeng Xiao, Jun Wang, Xiaohui Zhou, Qing Yang, Ping Zhang, Shu Li, Wen Xiong, Fei Yu, Qilin Wang, Cong-Yi MBD2 acts as a repressor to maintain the homeostasis of the Th1 program in type 1 diabetes by regulating the STAT1-IFN-γ axis |
title | MBD2 acts as a repressor to maintain the homeostasis of the Th1 program in type 1 diabetes by regulating the STAT1-IFN-γ axis |
title_full | MBD2 acts as a repressor to maintain the homeostasis of the Th1 program in type 1 diabetes by regulating the STAT1-IFN-γ axis |
title_fullStr | MBD2 acts as a repressor to maintain the homeostasis of the Th1 program in type 1 diabetes by regulating the STAT1-IFN-γ axis |
title_full_unstemmed | MBD2 acts as a repressor to maintain the homeostasis of the Th1 program in type 1 diabetes by regulating the STAT1-IFN-γ axis |
title_short | MBD2 acts as a repressor to maintain the homeostasis of the Th1 program in type 1 diabetes by regulating the STAT1-IFN-γ axis |
title_sort | mbd2 acts as a repressor to maintain the homeostasis of the th1 program in type 1 diabetes by regulating the stat1-ifn-γ axis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8738722/ https://www.ncbi.nlm.nih.gov/pubmed/34420035 http://dx.doi.org/10.1038/s41418-021-00852-6 |
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