Dnmt3a 和 Tet2 的功能丧失突变会导致动脉粥样硬化加速和巨噬细胞表型一致。
Loss-of-function mutations in Dnmt3a and Tet2 lead to accelerated atherosclerosis and concordant macrophage phenotypes.
发表日期：2023 Sep
作者：
Philipp J Rauch, Jayakrishnan Gopakumar, Alexander J Silver, Daniel Nachun, Herra Ahmad, Marie McConkey, Tetsushi Nakao, Marc Bosse, Thiago Rentz, Nora Vivanco Gonzalez, Noah F Greenwald, Erin F McCaffrey, Zumana Khair, Manu Gopakumar, Kameron B Rodrigues, Amy E Lin, Eti Sinha, Maia Fefer, Drew N Cohen, Amélie Vromman, Eugenia Shvartz, Galina Sukhova, Sean Bendall, Michael Angelo, Peter Libby, Benjamin L Ebert, Siddhartha Jaiswal
来源：
Epigenetics & Chromatin
摘要：
不确定潜能克隆造血 (CHIP) 的定义是，在不存在明显的血液恶性肿瘤的情况下，白细胞中存在与癌症相关的体细胞突变。它最常见的原因是表观遗传调节因子 DNMT3A 和 TET2 的功能丧失突变。 CHIP 容易导致人类血液恶性肿瘤和动脉粥样硬化性心血管疾病。在这里，我们证明，骨髓细胞中 Dnmt3a 的缺失会增加小鼠动脉粥样硬化，其程度与之前发现的 Tet2 缺失的程度相似。 Dnmt3a 的缺失增强了体外巨噬细胞的炎症，并在体内产生了独特的外膜巨噬细胞群，它将常驻巨噬细胞特征与炎症细胞因子特征融合在一起。这些变化令人惊讶地表现出 Tet2 缺失的影响。我们的结果确定了一个共同途径，通过丢失任一基因来促进先天免疫细胞激活增强，为这两种最常见的 CHIP 突变携带者的过度动脉粥样硬化疾病负担提供了生物学基础。© 2023。作者，拥有独家许可施普林格自然有限公司。
Clonal hematopoiesis of indeterminate potential (CHIP) is defined by the presence of a cancer-associated somatic mutation in white blood cells in the absence of overt hematological malignancy. It arises most commonly from loss-of-function mutations in the epigenetic regulators DNMT3A and TET2. CHIP predisposes to both hematological malignancies and atherosclerotic cardiovascular disease in humans. Here we demonstrate that loss of Dnmt3a in myeloid cells increased murine atherosclerosis to a similar degree as previously seen with loss of Tet2. Loss of Dnmt3a enhanced inflammation in macrophages in vitro and generated a distinct adventitial macrophage population in vivo which merges a resident macrophage profile with an inflammatory cytokine signature. These changes surprisingly phenocopy the effect of loss of Tet2. Our results identify a common pathway promoting heightened innate immune cell activation with loss of either gene, providing a biological basis for the excess atherosclerotic disease burden in carriers of these two most prevalent CHIP mutations.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.