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

DNA 甲基转移酶 3 α (DNMT3A) 和 TET 甲基胞嘧啶双加氧酶 2 (TET2) 的有害体细胞突变与造血细胞的克隆扩张和心血管疾病 (CVD) 的较高风险相关。在这里，我们研究了 DNMT3A 和 TET2 在正常人单核细胞来源的巨噬细胞 (MDM)、从具有DNMT3A或TET2突变的个体中分离的 MDM 以及从人动脉粥样硬化斑块中分离的巨噬细胞中的作用。我们发现，由于线粒体 DNA 完整性受损和 cGAS 信号传导激活，DNMT3A 或 TET2 功能丧失会导致 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 完整性，这取决于它们与TFAM基因调节区域的 RBPJ 和 ZNF143 的相互作用。这些发现表明，针对 cGAS-I 型 IFN 通路可能对降低 DNMT3A 或 TET2 突变患者的 CVD 风险具有治疗价值。