Journal Article
. 2014 Apr; 15(6):571-9.
doi: 10.1038/ni.2886.

The epigenetic regulator Uhrf1 facilitates the proliferation and maturation of colonic regulatory T cells

Yuuki Obata 1 Yukihiro Furusawa 2 Takaho A Endo 3 Jafar Sharif 4 Daisuke Takahashi 5 Koji Atarashi 6 Manabu Nakayama 7 Satoshi Onawa 5 Yumiko Fujimura 8 Masumi Takahashi 5 Tomokatsu Ikawa 9 Takeshi Otsubo 10 Yuki I Kawamura 10 Taeko Dohi 10 Shoji Tajima 11 Hiroshi Masumoto 12 Osamu Ohara 3 Kenya Honda 13 Shohei Hori 14 Hiroshi Ohno 15 Haruhiko Koseki 4 Koji Hase 16 
Affiliations
  • PMID: 24777532
  •     49 References
  •     74 citations

Abstract

Intestinal regulatory T cells (Treg cells) are necessary for the suppression of excessive immune responses to commensal bacteria. However, the molecular machinery that controls the homeostasis of intestinal Treg cells has remained largely unknown. Here we report that colonization of germ-free mice with gut microbiota upregulated expression of the DNA-methylation adaptor Uhrf1 in Treg cells. Mice with T cell-specific deficiency in Uhrf1 (Uhrf1(fl/fl)Cd4-Cre mice) showed defective proliferation and functional maturation of colonic Treg cells. Uhrf1 deficiency resulted in derepression of the gene (Cdkn1a) that encodes the cyclin-dependent kinase inhibitor p21 due to hypomethylation of its promoter region, which resulted in cell-cycle arrest of Treg cells. As a consequence, Uhrf1(fl/fl)Cd4-Cre mice spontaneously developed severe colitis. Thus, Uhrf1-dependent epigenetic silencing of Cdkn1a was required for the maintenance of gut immunological homeostasis. This mechanism enforces symbiotic host-microbe interactions without an inflammatory response.

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Busheng Xue, Jiansong Zhao, +3 authors, Yan Li.
Onco Targets Ther, 2019 Jan 23; 12. PMID: 30666134    Free PMC article.
Review.
BjussuLAAO-II induces cytotoxicity and alters DNA methylation of cell-cycle genes in monocultured/co-cultured HepG2 cells.
Ana Rita Thomazela Machado, Alexandre Ferro Aissa, +3 authors, Lusânia Maria Greggi Antunes.
J Venom Anim Toxins Incl Trop Dis, 2019 May 28; 25. PMID: 31131003    Free PMC article.
Immunomodulation by anticancer cell cycle inhibitors.
Giulia Petroni, Silvia C Formenti, Selina Chen-Kiang, Lorenzo Galluzzi.
Nat Rev Immunol, 2020 Apr 30; 20(11). PMID: 32346095    Free PMC article.
Review.
Bone Morphogenic Proteins Are Immunoregulatory Cytokines Controlling FOXP3+ Treg Cells.
Lauren M Browning, Caroline Miller, +6 authors, Piotr Kraj.
Cell Rep, 2020 Oct 08; 33(1). PMID: 33027660    Free PMC article.
Maintenance DNA methylation is essential for regulatory T cell development and stability of suppressive function.
Kathryn A Helmin, Luisa Morales-Nebreda, +9 authors, Benjamin D Singer.
J Clin Invest, 2020 Sep 09; 130(12). PMID: 32897881    Free PMC article.
UHRF1 downregulation promotes T follicular helper cell differentiation by increasing BCL6 expression in SLE.
Limin Liu, Longyuan Hu, +8 authors, Ming Zhao.
Clin Epigenetics, 2021 Feb 12; 13(1). PMID: 33568199    Free PMC article.
Single-nucleotide methylation specifically represses type I interferon in antiviral innate immunity.
Zheng-Jun Gao, Wen-Ping Li, +8 authors, Yi-Yuan Li.
J Exp Med, 2021 Feb 23; 218(3). PMID: 33616624    Free PMC article.
uhrf1 and dnmt1 Loss Induces an Immune Response in Zebrafish Livers Due to Viral Mimicry by Transposable Elements.
Elena Magnani, Filippo Macchi, +3 authors, Kirsten C Sadler.
Front Immunol, 2021 Apr 16; 12. PMID: 33854502    Free PMC article.
Epigenome-metabolome-microbiome axis in health and IBD.
Hajera Amatullah, Kate L Jeffrey.
Curr Opin Microbiol, 2020 Sep 14; 56. PMID: 32920333    Free PMC article.
Review.
PIP4Ks impact on PI3K, FOXP3, and UHRF1 signaling and modulate human regulatory T cell proliferation and immunosuppressive activity.
Alessandro Poli, Shidqiyyah Abdul-Hamid, +7 authors, Nullin Divecha.
Proc Natl Acad Sci U S A, 2021 Jul 28; 118(31). PMID: 34312224    Free PMC article.
Metabolic Controls on Epigenetic Reprogramming in Regulatory T Cells.
Jingli Lu, Yan Liang, +3 authors, Chengliang Zhang.
Front Immunol, 2021 Aug 24; 12. PMID: 34421930    Free PMC article.
Review.
Epigenetic regulation by gut microbiota.
Vivienne Woo, Theresa Alenghat.
Gut Microbes, 2022 Jan 11; 14(1). PMID: 35000562    Free PMC article.
Review.
Transcriptional changes in dendritic cells underlying allergen specific induced tolerance in a mouse model.
Rafael Nuñez, Maria Jose Rodriguez, +9 authors, Cristobalina Mayorga.
Sci Rep, 2022 Feb 20; 12(1). PMID: 35181694    Free PMC article.
Uhrf1 governs the proliferation and differentiation of muscle satellite cells.
Hiroshi Sakai, Yuichiro Sawada, +9 authors, Yuuki Imai.
iScience, 2022 Mar 05; 25(3). PMID: 35243267    Free PMC article.
Epigenetic Control of Regulatory T Cell Stability and Function: Implications for Translation.
Anthony M Joudi, Carla P Reyes Flores, Benjamin D Singer.
Front Immunol, 2022 Mar 22; 13. PMID: 35309306    Free PMC article.
Review.