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

By 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

Posted 04 Feb 2020
bioRxiv DOI: 10.1101/2020.02.03.926949 (published DOI: 10.1172/JCI137712)

Regulatory T (Treg) cells require Foxp3 expression and induction of a specific DNA hypomethylation signature during development, after which Treg cells persist as a self-renewing population that regulates immune system activation. Whether maintenance DNA methylation is required for Treg cell lineage development and stability and how methylation patterns are maintained during lineage self-renewal remain unclear. Here, we demonstrate that the epigenetic regulator 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 non-uniform loss of DNA methylation, derepression of inflammatory transcriptional programs, destabilization of the Treg cell lineage, spontaneous inflammation, and enhanced tumor immunity. These findings support a paradigm in which maintenance DNA methylation is required in distinct regions of the Treg cell genome for both lineage establishment and stability of identity and suppressive function.

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