Epigenetic regulation of cytokine gene expression and clinical applications in inflammatory diseases

2017 Fiscal Year Final Research Report

• Project/Area Number: 15K10987
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Emergency medicine
• Research Institution: Fukushima Medical University
• Principal Investigator: SEKIMATA MASAYUKI 福島県立医科大学, 医学部, 准教授 (80250190)
• Co-Investigator(Kenkyū-buntansha): 伊関 憲 福島県立医科大学, 医学部, 教授 (70332921) ; 関亦 明子 山形大学, 医学部, 准教授 (50321823)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: 炎症制御 / 遺伝子発現 / サイトカイン / クロマチン構造 / エピジェネティクス / エピゲノム編集 / シス調節領域 / 転写因子

Outline of Final Research Achievements

IL-22 is a cytokine that plays a pivotal role in regulating tissue homeostasis at barrier surfaces. Currently, the molecular mechanisms regulating Il22 gene expression are still unclear. Here, we have identified a crucial cis-regulatory element (CNS-32). We demonstrated that CNS-32 acts as an enhancer in reporter assays and contains binding motifs for Runx1 and RORγt. Mutation of these motifs significantly abrogated the reporter activity, suggesting a role for both factors in the control of enhancer-mediated Il22 expression. Overexpression of Runx1 promoted IL-22 production by inducing RORγt and IL-23 receptor, all critical to Th22 cell induction. Although Runx1 alone enhanced IL-22 production in Th22 cells, it was further enhanced in the presence of RORγt. Collectively, our results suggest that IL-22 production is controlled by a regulatory circuit in which Runx1 induces RORγt and then partners with RORγt to direct Il22 expression through their targeting of the Il22 enhancer.

Free Research Field

分子細胞生物学