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

Kathryn A Helmin ¹, Luisa Morales-Nebreda ¹, Manuel A Torres Acosta ¹, Kishore R Anekalla ¹, Shang-Yang Chen ¹, Hiam Abdala-Valencia ¹, Yuliya Politanska ¹, Paul Cheresh ¹, Mahzad Akbarpour ², Elizabeth M Steinert ¹, Samuel E Weinberg ¹, Benjamin D Singer ¹

Affiliations

¹ Division of Pulmonary and Critical Care Medicine, Department of Medicine.
² Department of Surgery.

PMID: 32897881
70 References
15 citations

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.

Keywords: Autoimmune diseases; Autoimmunity; Epigenetics; Immunology; T cells.

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