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

被引：58

作者：

Helmin, Kathryn A. ^{[1
]}

Morales-Nebreda, Luisa ^{[1
]}

Acosta, Manuel A. Torres ^{[1
]}

Anekalla, Kishore R. ^{[1
]}

Chen, Shang-Yang ^{[1
]}

Abdala-Valencia, Hiam ^{[1
]}

Politanska, Yuliya ^{[1
]}

Cheresh, Paul ^{[1
]}

Akbarpour, Mahzad ^{[2
]}

Steinert, Elizabeth M. ^{[1
]}

Weinberg, Samuel E. ^{[1
,3
]}

Singer, Benjamin D. ^{[1
,4
,5
]}

机构：

[1] Northwestern Univ, Feinberg Sch Med, Div Pulm & Crit Care Med, Dept Med, Chicago, IL 60611 USA

[2] Northwestern Univ, Feinberg Sch Med, Dept Surg, Chicago, IL 60611 USA

[3] Northwestern Univ, Feinberg Sch Med, Dept Pathol, Chicago, IL 60611 USA

[4] Northwestern Univ, Feinberg Sch Med, Dept Biochem & Mol Genet, Chicago, IL 60611 USA

[5] Northwestern Univ, Feinberg Sch Med, Simpson Querrey Inst Epigenet, Chicago, IL 60611 USA

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2020年 / 130卷 / 12期

关键词：

TRANSCRIPTION-FACTOR; FOXP3; EXPRESSION; UHRF1; DIFFERENTIATION; INFLAMMATION; PLASTICITY; DEPLETION; EFFECTOR; VARIANTS; BLOCKADE;

D O I：

10.1172/JCI137712

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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.

引用

页码：6571 / 6587

页数：17

共 70 条

[1] Regulatory T cells in the skin lesions and blood of patients with systemic sclerosis and morphoea [J].