缺失一个保守的 Gata2 增强子会损害造血内皮细胞的编程和成年斑马鱼的造血作用。
Deletion of a conserved Gata2 enhancer impairs haemogenic endothelium programming and adult Zebrafish haematopoiesis.
机构信息
MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DS, UK.
Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK.
出版信息
Commun Biol. 2020 Feb 13;3(1):71. doi: 10.1038/s42003-020-0798-3.
Gata2 is a key transcription factor required to generate Haematopoietic Stem and Progenitor Cells (HSPCs) from haemogenic endothelium (HE); misexpression of Gata2 leads to haematopoietic disorders. Here we deleted a conserved enhancer (i4 enhancer) driving pan-endothelial expression of the zebrafish gata2a and showed that Gata2a is required for HE programming by regulating expression of runx1 and of the second Gata2 orthologue, gata2b. By 5 days, homozygous gata2a larvae showed normal numbers of HSPCs, a recovery mediated by Notch signalling driving gata2b and runx1 expression in HE. However, gata2a adults showed oedema, susceptibility to infections and marrow hypo-cellularity, consistent with bone marrow failure found in GATA2 deficiency syndromes. Thus, gata2a expression driven by the i4 enhancer is required for correct HE programming in embryos and maintenance of steady-state haematopoietic stem cell output in the adult. These enhancer mutants will be useful in exploring further the pathophysiology of GATA2-related deficiencies in vivo.
Gata2 是一个关键的转录因子，它从造血内皮（HE）中生成造血干细胞和祖细胞（HSPCs）；Gata2 的异常表达会导致造血系统紊乱。在这里，我们删除了一个保守的增强子（i4 增强子），该增强子驱动斑马鱼 gata2a 的全内皮表达，研究表明 Gata2a 通过调节 runx1 和第二个 Gata2 同源物 gata2b 的表达来调控 HE 的编程。到第 5 天，纯合 gata2a 幼虫的 HSPCs 数量正常，这是由 Notch 信号通路介导的，它驱动 HE 中 gata2b 和 runx1 的表达而恢复的。然而，gata2a 成年鱼表现出水肿、易感染和骨髓细胞减少，与 GATA2 缺陷综合征中发现的骨髓衰竭一致。因此，由 i4 增强子驱动的 gata2a 表达对于胚胎中正确的 HE 编程和成年期稳态造血干细胞输出的维持是必需的。这些增强子突变体将有助于进一步探索 GATA2 相关缺陷的体内病理生理学。
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