Tet Proteins Regulate Neutrophil Granulation in Zebrafish through Demethylation of socs3b mRNA.
Tet Proteins Regulate Neutrophil Granulation in Zebrafish through Demethylation of socs3b mRNA.
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Tet蛋白通过socs3b mRNA的去甲基化调节斑马鱼中性粒细胞的颗粒形成。
DOI：
10.1016/j.celrep.2020.108632
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发表时间：
2021-01-12
期刊：
影响因子：
8.8
通讯作者：
Evans T
中科院分区：
文献类型：
--
作者：
Banks KM;Lan Y;Evans T
Tet 蛋白 (Tet1/2/3) 将 5-甲基胞嘧啶 (5mC) 转化为 5-羟甲基胞嘧啶 (5hmC)，启动主动去甲基化过程以调节基因表达。去甲基化主要在 DNA 背景下进行研究，但最近 Tet 酶也被证明可以介导 RNA 中 5mC 的去甲基化，作为表观转录组调节的额外水平。我们分析了复合 tet2/3 突变斑马鱼，发现 Tet 酶在颗粒化过程中原始和定形中性粒细胞成熟中的作用。转录谱分析显示 tet 突变中性粒细胞中细胞因子信号传导失调，包括 socs3b 的上调。我们发现 Tet 通常在颗粒化过程中使 socs3b mRNA 去甲基化，从而破坏转录物的稳定性，导致其下调。这一过程的失败会导致 socs3b mRNA 的积累，并在中性粒细胞成熟的这一关键步骤中抑制细胞因子信号传导。这项研究为 Tets 作为表观转录组调节酶提供了进一步的证据，并表明 Tet2/3 参与中性粒细胞成熟的调节。 Tet 蛋白以消除或阻断 DNA 甲基化而闻名。班克斯等人。表明斑马鱼的 tet2/3 突变体在原始和定形中性粒细胞的成熟方面存在缺陷。然而，该表型与 socs3b RNA 的超甲基化相关，导致 socs3b RNA 稳定性增强并阻断正常细胞因子信号传导。
Tet proteins (Tet1/2/3) convert 5-methylcytosine (5mC) to 5-hydroxy-methylcytosine (5hmC), initiating the process of active demethylation to regulate gene expression. Demethylation has been investigated primarily in the context of DNA, but recently Tet enzymes have also been shown to mediate demethylation of 5mC in RNA as an additional level of epitranscriptomic regulation. We analyzed compound tet2/3 mutant zebrafish and discovered a role for Tet enzymes in the maturation of primitive and definitive neutrophils during granulation. Transcript profiling showed dysregulation of cytokine signaling in tet mutant neutrophils, including upregulation of socs3b. We show that Tet normally demethylates socs3b mRNA during granulation, thereby destabilizing the transcript, leading to its downregulation. Failure of this process leads to accumulation of socs3b mRNA and repression of cytokine signaling at this crucial step of neutrophil maturation. This study provides further evidence for Tets as epitranscriptomic regulatory enzymes and implicates Tet2/3 in regulation of neutrophil maturation. Tet proteins are known for removing or blocking DNA methylation. Banks et al. show that zebrafish mutant for tet2/3 have defects in maturation of primitive and definitive neutrophils. However, the phenotype is associated with hypermethylation of socs3b RNA, leading to enhanced socs3b RNA stability and a block in normal cytokine signaling.
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影响因子：
8.8
作者：
Hussain S;Sajini AA;Blanco S;Dietmann S;Lombard P;Sugimoto Y;Paramor M;Gleeson JG;Odom DT;Ule J;Frye M
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作者：
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