Lim Jung-Yeon, Duttke Sascha H, Baker Turner S, Lee Jihye, Gambino Kristyne J, Venturini Nicholas J, Ho Jessica Sook Yuin, Zheng Simin, Fstkchyan Yesai S, Pillai Vinodh, Fajgenbaum David C, Marazzi Ivan, Benner Christopher, Byun Minji
Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
Department of Medicine, University of California, San Diego, La Jolla, CA.
J Exp Med. 2021 Jul 5;218(7). doi: 10.1084/jem.20202733. Epub 2021 May 10.
DNMT3A encodes an enzyme that carries out de novo DNA methylation, which is essential for the acquisition of cellular identity and specialized functions during cellular differentiation. DNMT3A is the most frequently mutated gene in age-related clonal hematopoiesis. As such, mature immune cells harboring DNMT3A mutations can be readily detected in elderly persons. Most DNMT3A mutations associated with clonal hematopoiesis are heterozygous and predicted to cause loss of function, indicating that haploinsufficiency is the predominant pathogenic mechanism. Yet, the impact of DNMT3A haploinsufficiency on the function of mature immune cells is poorly understood. Here, we demonstrate that DNMT3A haploinsufficiency impairs the gain of DNA methylation at decommissioned enhancers, while simultaneously and unexpectedly impairing DNA demethylation of newly activated enhancers in mature human myeloid cells. The DNA methylation defects alter the activity of affected enhancers, leading to abnormal gene expression and impaired immune response. These findings provide insights into the mechanism of immune dysfunction associated with clonal hematopoiesis and acquired DNMT3A mutations.
DNMT3A编码一种执行从头DNA甲基化的酶，这对于细胞分化过程中细胞特性和特殊功能的获得至关重要。DNMT3A是与年龄相关的克隆性造血中最常发生突变的基因。因此，在老年人中可以很容易地检测到携带DNMT3A突变的成熟免疫细胞。与克隆性造血相关的大多数DNMT3A突变是杂合的，预计会导致功能丧失，这表明单倍剂量不足是主要的致病机制。然而，DNMT3A单倍剂量不足对成熟免疫细胞功能的影响却知之甚少。在这里，我们证明DNMT3A单倍剂量不足会损害已停用增强子处DNA甲基化的增加，同时意外地损害成熟人类髓细胞中新激活增强子的DNA去甲基化。DNA甲基化缺陷改变了受影响增强子的活性，导致异常的基因表达和免疫反应受损。这些发现为与克隆性造血和获得性DNMT3A突变相关的免疫功能障碍机制提供了见解。
