美国加州大学Christopher K. Glass团队近期取得重要工作进展，他们研究发现DNA甲基转移酶3α和TET甲基胞嘧啶双加氧酶2抑制巨噬细胞中线粒体DNA介导的干扰素信号传导。相关论文2022年8月4日在线发表于《免疫》杂志上。

研究人员探讨了DNMT3A和TET2在正常人类单核细胞来源的巨噬细胞（MDM）、具有DNMT3A或TET2突变的个体来源的MDM以及人类动脉粥样硬化斑块来源的巨噬细胞中的作用。他们发现，由于线粒体DNA完整性受损和cGAS信号传导的激活，DNMT3A或TET2的功能丧失导致I型干扰素反应。DNMT3A和TET2通常通过调节转录因子A线粒体（TFAM）的表达来维持线粒体DNA的完整性，这取决于它们在TFAM基因的调节区域与RBPJ和ZNF143的相互作用。这些发现表明，靶向cGAS-I型IFN通路可能在降低DNMT3A或TET2突变患者的CVD风险方面具有治疗价值。

据介绍，DNA甲基转移酶3 α（DNMT3A）和TET甲基胞嘧啶双加氧酶2（TET2）的缺失体细胞突变，与造血细胞的克隆扩增和心血管疾病（CVD）的高风险相关。

附：英文原文

Title: DNA methyltransferase 3 alpha and TET methylcytosine dioxygenase 2 restrain mitochondrial DNA-mediated interferon signaling in macrophages

Author: Isidoro Cobo, Tiffany N. Tanaka, Kailash Chandra Mangalhara, Addison Lana, Calvin Yeang, Claudia Han, Johannes Schlachetzki, Jean Challcombe, Bethany R. Fixsen, Mashito Sakai, Rick Z. Li, Hannah Fields, Michal Mokry, Randy G. Tsai, Rafael Bejar, Koen Prange, Menno de Winther, Gerald S. Shadel, Christopher K. Glass

Issue&Volume: 2022-08-04

Abstract: Deleterious somatic mutations in DNA methyltransferase 3 alpha (DNMT3A) and TET mehtylcytosinedioxygenase 2 (TET2) are associated with clonal expansion of hematopoietic cells andhigher risk of cardiovascular disease (CVD). Here, we investigated roles of DNMT3Aand TET2 in normal human monocyte-derived macrophages (MDM), in MDM isolated fromindividuals with DNMT3A or TET2 mutations, and in macrophages isolated from human atherosclerotic plaques. We foundthat loss of function of DNMT3A or TET2 resulted in a type I interferon response dueto impaired mitochondrial DNA integrity and activation of cGAS signaling. DNMT3A andTET2 normally maintained mitochondrial DNA integrity by regulating the expressionof transcription factor A mitochondria (TFAM) dependent on their interactions with RBPJ and ZNF143 at regulatory regions of theTFAM gene. These findings suggest that targeting the cGAS-type I IFN pathway may havetherapeutic value in reducing risk of CVD in patients with DNMT3A or TET2 mutations.

DOI: 10.1016/j.immuni.2022.06.022

Source: https://www.cell.com/immunity/fulltext/S1074-7613(22)00295-3