Cis-element mutated in GATA2-dependent immunodeficiency governs hematopoiesis and vascular integrity
Cis-element mutated in GATA2-dependent immunodeficiency governs hematopoiesis and vascular integrity
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DOI：
10.1172/jci61623
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发表时间：
2012-10-01
影响因子：
15.9
通讯作者：
Bresnick, Emery H.
中科院分区：
文献类型：
--
作者：
Johnson, Kirby D.;Hsu, Amy P.;Bresnick, Emery H.
GATA 2单倍不足会导致人类免疫缺陷综合征，其特征是分枝杆菌感染、骨髓增生异常、淋巴水肿或再生障碍性贫血，进而发展为骨髓性白血病。GATA 2编码造血的主要调节因子，其也与内皮生物学相关。虽然致病突变通常发生在加塔-2 DNA结合域，我们确定了一个分枝杆菌感染和骨髓增生异常的患者谁有一个未表征的杂合缺失的GATA 2顺式元件组成的E盒和加塔基序。靶向删除等效鼠元件以产生纯合突变小鼠，其胚胎致死性晚于Gata 2基因敲除、造血干/祖细胞耗竭和血管完整性受损的情况。杂合突变小鼠是可行的，但胚胎表现出缺陷的永久性，但不是原始的，造血干/祖细胞活性和减少Gata 2及其靶基因的表达。机制分析显示，内皮细胞转录组被破坏，血管完整性丧失。因此，在人免疫缺陷中被破坏的复合元件对于在胎肝中建立鼠造血干/祖细胞区室和对于基本的血管过程是必需的。
Haploinsufficiency for GATA2 causes human immunodeficiency syndromes characterized by mycobacterial infection, myelodysplasia, lymphedema, or aplastic anemia that progress to myeloid leukemia. GATA2 encodes a master regulator of hematopoiesis that is also linked to endothelial biology. Though the disease-causing mutations commonly occur in the GATA-2 DNA binding domain, we identified a patient with mycobacterial infection and myelodysplasia who had an uncharacterized heterozygous deletion in a GATA2 cis-element consisting of an E-box and a GATA motif. Targeted deletion of the equivalent murine element to yield homozygous mutant mice revealed embryonic lethality later than occurred with global Gata2 knockout, hematopoietic stem/progenitor cell depletion, and impaired vascular integrity. Heterozygous mutant mice were viable, but embryos exhibited deficits in definitive, but not primitive, hematopoietic stem/progenitor activity and reduced expression of Gata2 and its target genes. Mechanistic analysis revealed disruption of the endothelial cell transcriptome and loss of vascular integrity. Thus, the composite element disrupted in a human immunodeficiency is essential for establishment of the murine hematopoietic stem/progenitor cell compartment in the fetal liver and for essential vascular processes.