Journal Article
. 2020 Sep; 130(12):6571-6587.
doi: 10.1172/JCI137712.

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 
  • PMID: 32897881
  •     70 References
  •     15 citations


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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