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- Title
Maintenance DNA methylation is essential for regulatory T cell development and stability of suppressive function.
- Authors
Helmin, Kathryn A.; Morales-Nebreda, Luisa; Torres Acosta, Manuel A.; Anekalla, Kishore R.; Shang-Yang Chen; Abdala-Valencia, Hiam; Politanska, Yuliya; Cheresh, Paul; Akbarpour, Mahzad; Steinert, Elizabeth M.; Weinberg, Samuel E.; Singer, Benjamin D.; Acosta, Manuel A Torres; Chen, Shang-Yang
- 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.
- Subjects
SUPPRESSOR cells; DNA methylation; CD25 antigen; T cells; IMMUNE system; PROTEINS; ANIMAL experimentation; ENZYMES; RESEARCH funding; MICE
- Publication
Journal of Clinical Investigation, 2020, Vol 130, Issue 12, p1
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI137712