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Maintenance DNA methylation is essential for regulatory T cell development and stability of suppressive function
Kathryn A. Helmin, … , Samuel E. Weinberg, Benjamin D. Singer
Kathryn A. Helmin, … , Samuel E. Weinberg, Benjamin D. Singer
Published September 8, 2020
Citation Information: J Clin Invest. 2020;130(12):6571-6587. https://doi.org/10.1172/JCI137712.
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Research Article Autoimmunity Immunology

Maintenance DNA methylation is essential for regulatory T cell development and stability of suppressive function

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Abstract

Tregs require Foxp3 expression and induction of a specific DNA hypomethylation signature during development, after which Tregs persist as a self-renewing population that regulates immune system activation. Whether maintenance DNA methylation is required for Treg lineage development and stability and how methylation patterns are maintained during lineage self-renewal remain unclear. Here, we demonstrate that the epigenetic regulator ubiquitin-like with plant homeodomain and RING finger domains 1 (Uhrf1) is essential for maintenance of methyl-DNA marks that stabilize Treg cellular identity by repressing effector T cell transcriptional programs. Constitutive and induced deficiency of Uhrf1 within Foxp3+ cells resulted in global yet nonuniform loss of DNA methylation, derepression of inflammatory transcriptional programs, destabilization of the Treg lineage, and spontaneous inflammation. These findings support a paradigm in which maintenance DNA methylation is required in distinct regions of the Treg genome for both lineage establishment and stability of identity and suppressive function.

Authors

Kathryn A. Helmin, Luisa Morales-Nebreda, Manuel A. Torres Acosta, Kishore R. Anekalla, Shang-Yang Chen, Hiam Abdala-Valencia, Yuliya Politanska, Paul Cheresh, Mahzad Akbarpour, Elizabeth M. Steinert, Samuel E. Weinberg, Benjamin D. Singer

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Figure 1

Treg-specific Uhrf1-deficient mice spontaneously develop a fatal inflammatory disorder.

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Treg-specific Uhrf1-deficient mice spontaneously develop a fatal inflamm...
(A) Survival curves of littermate control (Uhrf1+/flFoxp3YFP-Cre, n = 9) and Uhrf1fl/flFoxp3YFP-Cre (n = 14) mice compared using the log-rank (Mantel-Cox) test. (B) Gross photographs of 3- to 4-week-old littermate and Uhrf1fl/flFoxp3YFP-Cre mice along with photomicrographs of skin. Scale bars: 100 μm. (C) Photomicrographic survey of organ pathology. Scale bars: 100 μm. (D) CD3ε+ T cell subsets in selected organs. For lung, n = 5 (littermate) and n = 10 (Uhrf1fl/flFoxp3YFP-Cre); for liver, n = 6 (littermate) and n = 4 (Uhrf1fl/flFoxp3YFP-Cre); for kidney, n = 6 (littermate) and n = 4 (Uhrf1fl/flFoxp3YFP-Cre); for colon, n = 3 (littermate and Uhrf1fl/flFoxp3YFP-Cre). (E) Cytokine profile of splenic CD3ε+CD4+ T cells following ex vivo stimulation with phorbol 12-myristate 13-acetate and ionomycin for 4 hours in the presence of brefeldin A. Representative contour plots and summary data are shown. n = 5 per group. Summary plots show all data points with mean and SD. *q < 0.05; **q < 0.01; †q < 0.001; ‡q < 0.0001; NS, not significant by the 2-stage linear step-up procedure of Benjamini, Krieger, and Yekutieli with Q = 5%; exact q values are in Supplemental Data. See Supplemental Table 3 for fluorochrome abbreviations.

Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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