Tet2 restrains inflammatory gene expression in macrophages
Tet2 restrains inflammatory gene expression in macrophages
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DOI：
10.1016/j.exphem.2017.08.001
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发表时间：
2017-11-01
影响因子：
2.6
通讯作者：
Rauh, Michael J.
中科院分区：
文献类型：
--
作者：
Cull, Alyssa H.;Snetsinger, Brooke;Rauh, Michael J.
泰特甲基胞嘧啶双加氧酶2（TET 2）是克隆性造血潜能不确定（CHIP）和髓系肿瘤（包括骨髓增生异常综合征（MDS）和慢性粒单核细胞白血病（CMML））中最早和最频繁突变的基因之一。TET 2催化5-甲基胞嘧啶氧化为5-羟甲基胞嘧啶，导致DNA去甲基化，并且还通过招募组蛋白修饰剂来影响转录。失活TET 2突变导致表观遗传失调、克隆造血干细胞（HSC）优势和单核细胞谱系偏斜。在这里，我们发现Tet 2是小鼠巨噬细胞（M Phi）分化中最高表达的泰特酶。Tet 2转录进一步诱导脂多糖（LPS），但不是白细胞介素（IL）-4，刺激，可能在核因子κ β依赖性的方式。Tet 2的丢失并不影响早期的LPS基因反应在体外，但增加11-6，和精氨酸酶I（Argl）mRNA的表达在刺激骨髓来源的M Phi s（BMM Phi s）的后期阶段。Tet 2缺陷的腹膜M Phi s，然而，表现出深刻的，与体内炎症状态相关的LPS诱导的基因的组成型表达。与此相反，Tet 2缺陷并没有影响替代M Phi基因的表达显着响应IL-4。这些结果表明在体外和体内不存在Tet 2的情况下炎症的消退受损。我们还首次检测了来自MDS和CMML患者的BMM Phi中的TET 2突变，并测定了它们对LPS应答的影响，包括它们对人IL-6表达的潜在影响。我们的研究结果表明，Tet 2抑制小鼠M Phi s和小鼠的炎症，提高了Mclis中TET 2功能丧失可能改变患有TET 2突变CHIP的大型老年人群和TET 2突变骨髓癌患者的免疫环境的可能性。(C)2017 ISEH血液学和干细胞学会。爱思唯尔公司出版
Tet methylcytosine dioxygenase 2 (TET2) is one of the earliest and most frequently mutated genes in clonal hematopoiesis of indeterminate potential (CHIP) and myeloid cancers, including myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). TET2 catalyzes the oxidation of 5-methylcytosine to 5-hydroxymethylcytosine, leading to DNA demethylation, and also affects transcription by recruiting histone modifiers. Inactivating TET2 mutations cause epigenetic dysregulation, clonal hematopoietic stem cell (HSC) dominance, and monocytic lineage skewing. Here, we found that Tet2 was the most highly expressed Tet enzyme in murine macrophage (M Phi) differentiation. Tet2 transcription was further induced by lipopolysaccharide (LPS), but not interleukin (IL)-4, stimulation, potentially in a nuclear factor kappa beta-dependent manner. Tet2 loss did not affect early LPS gene responses in vitro, but increased 11-6, and Arginase I (Argl) mRNA expression at later stages of stimulation in bone-marrow-derived M Phi s (BMM Phi s). Tet2- deficient peritoneal M Phi s, however, demonstrated profound, constitutive expression of LPS-induced genes associated with an inflammatory state in vivo. In contrast, Tet2 deficiency did not affect alternative M Phi gene expression significantly in response to IL-4. These results suggested impaired resolution of inflammation in the absence of Tet2 both in vitro and in vivo. For the first time, we also detected TET2 mutations in BMM Phi s from MDS and CMML patients and assayed their effects on LPS responses, including their potential influence on human IL-6 expression. Our results show that Tet2 restrains inflammation in murine M Phi s and mice, raising the possibility that loss of TET2 function in Mclis may alter the immune environment in the large elderly population with TET2-mutant CHIP and in TET2-mutant myeloid cancer patients. (C) 2017 ISEH Society for Hematology and Stem Cells. Published by Elsevier Inc.