RNF4 regulates zebrafish granulopoiesis through the DNMT1‐C/EBPα axis
RNF4 regulates zebrafish granulopoiesis through the DNMT1‐C/EBPα axis
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DOI：
10.1096/fj.201701450rr
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发表时间：
2018-04
期刊：
影响因子：
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通讯作者：
Luxiang Wang;Xiaohui Liu;Haihong Wang;Hao Yuan;Saijuan Chen;Zhu Chen;H. Thé;Jun Zhou;Jun Z
中科院分区：
文献类型：
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作者：
Luxiang Wang;Xiaohui Liu;Haihong Wang;Hao Yuan;Saijuan Chen;Zhu Chen;H. Thé;Jun Zhou;Jun Z
RING finger protein 4（RNF 4）是一种多功能的小泛素相关修饰物（SUMO）靶向的泛素E3连接酶（STUbL），广泛表达于所有组织中，主要参与DNA修复、染色质和转录调控。虽然RNF 4与造血系统疾病有关，但其在造血发育过程中的个体发生作用仍未被发现。我们利用转录激活因子样效应核酸酶技术构建了斑马鱼rnf 4基因敲除系，以研究rnf 4在造血过程中的作用。RNF 4缺陷的斑马鱼胚胎在原始和最终造血过程中表现出中性粒细胞数量急剧减少。机制研究表明，通过SUMO化DNA甲基转移酶1（DNMT 1）启动子超甲基化抑制关键粒细胞激活因子CCAAT/增强子结合蛋白α（c/ebpα）是rnf 4缺陷斑马鱼粒细胞生成受损的主要原因。此外，我们首次将DNMT 1鉴定为RNF 4的潜在新STUbL底物，敲除dnmt 1在很大程度上恢复了raf 4缺陷斑马鱼中的原始和确定性粒细胞生成。总的来说，RNF 4通过调节DNMT 1-C/EBPα功能轴对斑马鱼的粒细胞生成是不可或缺的。Wang，L.，美国，刘，X.，王，H.，袁，H.，陈淑仪，陈志，de The，H.，周杰，Zhu，J. RNF 4通过DNMT 1-C/EBPα轴调节斑马鱼粒细胞生成。FASEB J. 32，4930-4940（2018）。www.fasebj.org
RING finger protein 4 (RNF4) is a multifunctional small ubiquitin‐related modifier (SUMO)‐targeted ubiquitin E3 ligase (STUbL) ubiquitously expressed in all tissues, and which mainly participates in DNA repair and in chromatin and transcriptional regulation. Although RNF4 has been implicated in hematopoietic disorders, its ontogenic role during hematopoietic development remains undiscovered. We generated a zebrafish rnf4 knockout line by using transcription activator–like effector nucleases technology to address the impact of rnf4 during hematopoiesis. Rnf4‐deficient zebrafish embryos exhibited sharply decreased neutrophils numbers during both primitive and definitive hematopoiesis. Mechanistic studies revealed that repression of the key granulocytic activator, CCAAT/enhancer‐binding protein α (c/ebpα), via promoter hypermethylation by SUMOylated DNA methyltransferase 1 (DNMT1) was the main cause of impaired granulopoiesis in rnf4‐deficient zebrafish. In addition, for the first time, we identified DNMT1 as a potential new STUbL substrate of RNF4, with knockdown of dnmt1 largely restoring primitive and definitive granulopoiesis in raf4‐deficient zebrafish. Collectively, RNF4 is indispensable for zebrafish granulopoiesis through regulation of the DNMT1‐C/EBPα functional axis.—Wang, L., Liu, X., Wang, H., Yuan, H., Chen, S., Chen, Z., de The, H., Zhou, J., Zhu, J. RNF4 regulates zebrafish granulopoiesis through the DNMT1‐C/EBPα axis. FASEB J. 32, 4930–4940 (2018). www.fasebj.org