美国国立卫生研究院NHLBI 赵可吉和NCI吴船团队合作提出，通过远端沉默子CNS-28抑制干扰素-γ (IFN-γ)表达以维持组织稳态。相关论文于2023年4月10日发表于国际顶尖学术期刊《免疫》杂志上。

通过检测Ifng位点内先天性CD4+ T细胞中H3K4me1组蛋白修饰，他们发现了一种抑制Ifng表达的沉默子(CNS-28)。在机制上，CNS-28通过减少Ifng位点内的增强子-启动子相互作用来维持Ifng沉默，这种相互作用依赖于GATA3，但不依赖于T-bet。CNS-28在功能上抑制NK细胞、CD4+细胞和CD8+ T细胞在先天和适应性免疫反应中的Ifng转录。

此外，CNS-28缺乏导致IFN-γ表达升高，Th1和Th2模式改变，从而抑制2型反应。因此，CNS-28活性通过与Ifng基因位点内的其他调节顺式元件合作来确保免疫细胞的静止，以最大限度地减少自身免疫。

据悉，IFN-γ是哺乳动物应对病毒或细胞内细菌感染的关键细胞因子。虽然许多增强子被描述为促进IFN-γ反应，但据人们所知，还没有发现Ifng基因的沉默子。

附：英文原文

Title: Restraint of IFN-γ expression through a distal silencer CNS–28 for tissue homeostasis

Author: Kairong Cui, Zuojia Chen, Yaqiang Cao, Shuai Liu, Gang Ren, Gangqing Hu, Difeng Fang, Danping Wei, Chengyu Liu, Jinfang Zhu, Chuan Wu, Keji Zhao

Issue&Volume: 2023-04-10

Abstract: Interferon-γ (IFN-γ) is a key cytokine in response to viral or intracellular bacterialinfection in mammals. While a number of enhancers are described to promote IFN-γ responses,to the best of our knowledge, no silencers for the Ifng gene have been identified. By examining H3K4me1 histone modification in naive CD4+ T cells within Ifng locus, we identified a silencer (CNS–28) that restrains Ifng expression. Mechanistically, CNS–28 maintains Ifng silence by diminishing enhancer-promoter interactions within Ifng locus in a GATA3-dependent but T-bet-independent manner. Functionally, CNS–28 restrainsIfng transcription in NK cells, CD4+ cells, and CD8+ T cells during both innate and adaptive immune responses. Moreover, CNS–28 deficiencyresulted in repressed type 2 responses due to elevated IFN-γ expression, shiftingTh1 and Th2 paradigm. Thus, CNS–28 activity ensures immune cell quiescence by cooperatingwith other regulatory cis elements within the Ifng gene locus to minimize autoimmunity.

DOI: 10.1016/j.immuni.2023.03.006

Source: https://www.cell.com/immunity/fulltext/S1074-7613(23)00126-7