Overlapping Requirements for Tet2 and Tet3 in Normal Development and Hematopoietic Stem Cell Emergence.
Overlapping Requirements for Tet2 and Tet3 in Normal Development and Hematopoietic Stem Cell Emergence.
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Tet2和Tet3在正常发育及造血干细胞产生中的重叠需求
DOI：
10.1016/j.celrep.2015.07.025
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发表时间：
2015-08-18
期刊：
影响因子：
8.8
通讯作者：
Goll MG
中科院分区：
文献类型：
--
作者：
Li C;Lan Y;Schwartz-Orbach L;Korol E;Tahiliani M;Evans T;Goll MG
Tet家族的甲基胞嘧啶双加氧酶(Tet1、TET2和Tet3)将5-甲基胞嘧啶转化为5-羟甲基胞嘧啶。到目前为止，Tet家族成员之间的功能重叠还没有在胚胎发育的背景下进行系统的研究。为了阐明Tet酶在发育过程中重叠的可能性，我们对斑马鱼Tet1、TET2和Tet3的同源基因进行了突变，并检测了单突变、双突变和三突变基因型。在这里，我们确定TET2和Tet3是斑马鱼胚胎中主要的5-甲基胞嘧啶双加氧酶，并揭示了在造血干细胞(HSC)出现过程中对TET2和Tet3的联合需求。我们证明了在HSC出现之前，血液内皮细胞中的Notch信号受TET2/3调节，并表明恢复下游gata2b/scl/RUNX1转录网络的表达可以挽救TET2/3双突变幼虫中的HSCs。我们的结果揭示了TET基因在胚胎发育过程中的基本重叠功能，并揭示了5hmC在调节HSC产生方面的需求。
The Tet family of methylcytosine dioxygenases (Tet1, Tet2 and Tet3) convert 5-methylcytosine to 5-hydroxymethylcytosine. To date, functional overlap among Tet family members has not been examined systematically in the context of embryonic development. To clarify the potential for overlap among Tet enzymes during development, we mutated the zebrafish orthologs of Tet1, Tet2 and Tet3, and examined single, double and triple mutant genotypes. Here, we identify Tet2 and Tet3 as the major 5-methylcytosine dioxygenases in the zebrafish embryo and uncover a combined requirement for Tet2 and Tet3 in hematopoietic stem cell (HSC) emergence. We demonstrate that Notch signaling in the hemogenic endothelium is regulated by Tet2/3 prior to HSC emergence and show that restoring expression of the downstream gata2b/scl/runx1 transcriptional network can rescue HSCs in tet2/3 double mutant larvae. Our results reveal essential, overlapping functions for tet genes during embryonic development and uncover a requirement for 5hmC in regulating HSC production.