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.
Original language | English (US) |
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Journal | Journal of Clinical Investigation |
Volume | 130 |
Issue number | 12 |
DOIs | |
State | Published - Dec 1 2020 |
Funding
LMN was supported by NIH awards T32HL076139 and F321H27L.1 M5T1AA was supported by NIH award T32GM008152. KRA was supported by the D. aCvuidg eWll and Christina Enroth-Cugell Fellowship. BDS was supported by NIH awards K08HL128867, U19AI135964, and R01HL149883 and the Francsis PFaarmkeilry BF.o Furnadnactiiso nR’esearch Opportunity AwardT. he content is solely the responsibility of the authors and does not necefiscsiaalr ivlyie rwesp roefs tehnet ftuhned oinf g sources.e W wish to acknowledge the Northwestern University Flow Cytometry Core FacilityThe BD supported by CA060553. FACSAria SOsRyPstem was purchased with the support1 o9f9 S61. 0eWO aDls0o1 wish to acknowledge the Northwestern University RNA-Seq Center/Genomics Lab of the Pulmonary and Critical Care Medicine and Rheumatology Divisions. Histology services were provided by the Northwestern University Mouse Histology and, wPhheicnho itsy psiunpgp Loartbeodr abtyory P30CA060553 awarded to the Robert H. Lurie Comprehen.s This research was supported in part through theive Cancer Center computational resources fa cnodn strtiabfutions provided by the Genomics Co,m wphuitcehr iCs lujosintetlry supported by the Feinberg School of Medicine, the Center for Genetic Medisc inDee,p aanrtdm Feenitn obfe Brgio’ chemistry and Molecular Genetics, thefi cOef of the Provost, ftihcee Ofofr Research, and Northwestern TIencfohrnmoalot.igo The Genomics Computeyn Cluster is part of Quest, Northwesterns hUingihv epresriftoy’rmance computi,n wg iftahc tihlitey purpose of advancing research in genomics. LMN was supported by NIH awards T32HL076139 and F32HL151127. MATA was supported by NIH award T32GM008152. KRA was supported by the David W. Cugell and Christina Enroth-Cugell Fellowship. BDS was supported by NIH awards K08HL128867, U19AI135964, and R01HL149883 and the Francis Family Foundation?s Parker B. Francis Research Opportunity Award. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding sources. We wish to acknowledge the Northwestern University Flow Cytometry Core Facility supported by CA060553. The BD FACSAria SORP system was purchased with the support of S10OD011996. We also wish to acknowledge the Northwestern University RNA-Seq Center/Genomics Lab of the Pulmonary and Critical Care Medicine and Rheumatology Divisions. Histology services were provided by the Northwestern University Mouse Histology and Phenotyping Laboratory, which is supported by P30CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. This research was supported in part through the computational resources and staff contributions provided by the Genomics Computer Cluster, which is jointly supported by the Feinberg School of Medicine, the Center for Genetic Medicine, and Feinberg?s Department of Biochemistry and Molecular Genetics, the Office of the Provost, the Office for Research, and Northwestern Information Technology. The Genomics Compute Cluster is part of Quest, Northwestern University?s high performance computing facility, with the purpose of advancing research in genomics.
ASJC Scopus subject areas
- General Medicine