医学免疫学国家重点实验室主任曹雪涛院士团队发现,DNA修饰酶Tet2分子可以通过调控RNA修饰的新方式,促进机体增加天然免疫细胞的数量和功能,以应对病原体感染及其炎症反应。该发现不仅从免疫学角度为机体抵抗病原体感染的天然免疫机制提出了新观点,也在表观机制层面揭示了Tet2参与基因表达转录后调控的新模式,为有效防治感染性疾病和控制炎症性疾病提供了新思路和潜在药物研发靶标。相关论文1月25日刊登于《自然》杂志。
天然免疫系统一旦感知到病原体感染,会马上诱导产生大量天然免疫细胞并通过促发炎症反应以期清除入侵的病原体,但天然免疫与炎症反应是一把双刃剑,过度活化会损伤机体。如何有效适度地平衡调控天然免疫与炎症反应的发生与终止,是免疫学领域的一个重大科学问题。
曹雪涛团队从表观转录组的角度研究了RNA修饰在天然免疫与炎症中的作用,发现DNA羟甲基化酶Tet2能够作为一种RNA结合蛋白作用于免疫分子mRNA水平,进而促进感染状态下机体外周血天然免疫细胞的数量增加,利于病原体的清除。
研究人员利用紫外交联免疫共沉淀结合高通量测序(CLIP-seq)和单个核苷酸分辨率的全转录组RNA甲基化测序等RNA相关组学技术,进一步在分子机制上揭示了Tet2能够直接结合免疫信号通路负调控分子Socs3的mRNA的3`-UTR,并抑制该区域RNA胞嘧啶甲基化,促进了Socs3 mRNA的降解,达到了负负得正的效果,促进了机体在感染早期天然免疫细胞的发生及其功能。(来源:中国科学报 唐凤)
Tet2 promotes pathogen infection-induced myelopoiesis through mRNA oxidation
Abstract
Varieties of RNA modification form the epitranscriptome for post-transcriptional regulation1. 5-Methylcytosine (5-mC) is a sparse RNA modification in messenger RNA (mRNA) under physiological conditions2. The function of RNA 5-hydroxymethylcytosine (5-hmC) oxidized by ten-eleven translocation (Tet) proteins inDrosophilahas been revealed more recently3,4. However, the turnover and function of 5-mC in mammalian mRNA have been largely unknown. Tet2 suppresses myeloid malignancies mostly in an enzymatic activity-dependent manner5, and is important in resolving inflammatory response in an enzymatic activity-independent way6. Myelopoiesis is a common host immune response in acute and chronic infections; however, its epigenetic mechanism needs to be identified. Here we demonstrate that Tet2 promotes infection-induced myelopoiesis in an mRNA oxidation-dependent manner through Adar1-mediated repression of Socs3 expression at the post-transcription level. Tet2 promotes both abdominal sepsis-induced emergency myelopoiesis and parasite-induced mast cell expansion through decreasing mRNA levels of Socs3, a key negative regulator of the JAK–STAT pathway that is critical for cytokine-induced myelopoiesis. Tet2 represses Socs3 expression through Adar1, which binds and destabilizes Socs3 mRNA in a RNA editing-independent manner. For the underlying mechanism of Tet2 regulation at the mRNA level, Tet2 mediates oxidation of 5-mC in mRNA. Tet2 deficiency leads to the transcriptome-wide appearance of methylated cytosines, including ones in the 3′ untranslated region of Socs3, which influences double-stranded RNA formation for Adar1 binding, probably through cytosine methylation-specific readers, such as RNA helicases. Our study reveals a previously unknown regulatory role of Tet2 at the epitranscriptomic level, promoting myelopoiesis during infection in the mammalian system by decreasing 5-mCs in mRNAs. Moreover, the inhibitory function of cytosine methylation on double-stranded RNA formation and Adar1 binding in mRNA reveals its new physiological role in the mammalian system.