The Epigenetic Regulator UHRF1 Facilitates the Proliferation and Maturation of Colonic Regulatory T Cells

Obata Y, Furusawa Y, Endo TA, Sharif J, Takahashi D, Atarashi K, Nakayama M, Onawa S, Fujimura Y, Takahashi M, Ikawa T, Otsubo T, Kawamura YI, Dohi T, Tajima S, Masumoto H, Ohara O, Honda K, Hori S, Ohno H, Koseki H, Hase K.

Nat Immunol. 2014 Jun;15(6):571-9. doi: 10.1038/ni.2886. Epub 2014 Apr 28.

From Left to Right: Yumiko Fujimara, Yukihiro Furusawa, Yuuki Obata, Koji Hase

From Left to Right: Yumiko Fujimara, Yukihiro Furusawa, Yuuki Obata, and Koji Hase

Mammalian neonate is exposed to a whole host of environmental microbes, some of which colonize the mucosal surfaces such as the distal intestine. Despite such a tremendous microbial burden in close proximity to the intestinal epithelial cells, the colonizing microbiota seldom causes inflammatory diseases. Intestinal regulatory T (Treg) cells are necessary for suppression of excessive immune response to commensal bacteria. In this study, we found that bacterial colonization early in life induces expansion and functional maturation of Treg cells in the colon. During this process, the DNA methylation adaptor Uhrf1 is upregulated in colonic Treg cells. Cd4creUhrf1fl/fl were defective in proliferation and functional maturation of colonic Treg cells. Uhrf1 deficiency de-repressed cyclin-dependent kinase inhibitor Cdkn1a due to hypomethylation of its promoter region, resulting in cell-cycle arrest of Treg cells. As a consequence, Cd4creUhrf1fl/fl mice spontaneously developed severe colitis. We therefore reasoned that Uhrf1-dependent regulation of Treg proliferation via this epigenetic mechanism is essential for the containment of the inflammatory response to gut microbiota. This mechanism enforces symbiotic host-microbe interactions without an inflammatory response. PubMed:24777532