Commensal microbiota maintains gut homeostasis through epigenetic modification

• Project/Area Number: 24890293
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Immunology
• Research Institution: The University of Tokyo
• Principal Investigator: FURUSAWA Yukihiro 東京大学, 医科学研究所, 特任助教 (80632306)
• Research Collaborator: ENDO Takaho 理化学研究所, 統合生命医科学研究所統合ゲノミクスグループ, 上級研究員 (40384862)
• Project Period (FY): 2012-08-31 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: エピジェネティクス / 制御性T細胞 / DNAメチル化 / 炎症性腸疾患 / 炎症生腸疾患

Research Abstract

Intestinal regulatory T (Treg) cells are necessary for suppression of excessive immune response to commensal bacteria. However, the molecular machinery controlling intestinal Treg cell homeostasis remains largely unknown. Here we report that colonization of germ-free mice with gut microbiota upregulated the expression of the DNA methylation adaptor Uhrf1 in Treg cells. Cd4creUhrf1fl/fl mice 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. Thus, Uhrf1-dependent epigenetic silencing of Cdkn1a is required for the maintenance of gut immune homeostasis. This mechanism enforces symbiotic host-microbe interactions without an inflammatory response.

Research Products

• [Journal Article] Epigenetic regulator Uhrf1 is critical for functional expansion of colonic regulatory T cells (2014)
  • Author(s): Obata Y, Furusawa Y , Endo TA, Sharif J, Takahashi D, Atarashi K, Onawa S, Fujimura Y, Takahashi M, Ikawa T, Otsubo T, Kawamura YI, Dohi T, Tajima S, Ohara O, Honda K, Hori S, Ohno H, Koseki H, Hase K
  • Journal Title: Nat. Immunol Volume: (in press)
• [Journal Article] The epigenetic regulator Uhrf1 facilitates proliferation and maturation of colonic regulatory T cells (2014)
  • Author(s): Yuuki Obata*, Yukihiro Furusawa*, Takaho A. Endo, Jafar Sharif, Daisuke Takahashi, Koji Atarashi, Manabu Nakayama, Satoshi Onawa, Yumiko Fujimura, Masumi Takahashi, Tomokatsu Ikawa, Takeshi Otsubo, Yuki I. Kawamura, Taeko Dohi, Shoji Tajima, Osamu Ohara, Kenya Honda, Shohei Hori, Hiroshi Ohno, Haruhiko Koseki and Koji Hase. 【* : 筆頭筆者】
  • Journal Title: Nature Immunology Volume: 15 Issue: 6 Pages: 571-579
  • DOI: 10.1038/ni.2886
  • Peer Reviewed / Open Access
• [Presentation] Commensal microbiota shapes gut immune system through epigenetic modification (2013)
  • Author(s): Furusawa Y, Obata Y, Sharif J, Hori S, Ohno H, Koseki H, Hase K
  • Organizer: International Congress of Mucosal Immunology
  • Place of Presentation: Vancouver, Canada
• [Presentation] Commensal microbiota shapes the gut immune system through epigenetic modifications (2013)
  • Author(s): Yukihiro Furusawa, Yuuki Obata, Jafar Sharif, Shohei Hori, Hiroshi Ohno, Haruhiko Koseki, Koji Hase
  • Organizer: International Congress of Mucosal Immunology (ICMI 2013)
  • Place of Presentation: Vancouver, Canada
• [Presentation] Commensal microbiota shapes the gut immune system through epigenetic modifications (2012)
  • Author(s): 古澤 之裕
  • Organizer: IEIIS2012
  • Place of Presentation: 東京
• [Remarks] 古澤之裕 特任助教、Nature Immunology Award 受賞
  • URL: http://www.ims.u-tokyo.ac.jp/imsut/jp/research/award/_nature_immunology_award_poste.php