Dynamic regulation of Gata1 expression during the maturation of conventional dendritic cells
Dynamic regulation of Gata1 expression during the maturation of conventional dendritic cells
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DOI：
10.1016/j.exphem.2010.03.006
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发表时间：
2010-06-01
影响因子：
2.6
通讯作者：
Migliaccio, Anna Rita
中科院分区：
文献类型：
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作者：
Kozma, Gergely T.;Martelli, Fabrizio;Migliaccio, Anna Rita
目标.为了鉴定在常规树突状细胞（cDC）中驱动Gata 1表达的调控序列。研究Gata 1（low）突变小鼠和野生型小鼠cDCs中Gata 1、Gata 1靶基因和超敏位点（HS）2（eosinophil-specific enhancer）驱动的绿色荧光蛋白（GFP）报告基因的数量和表达水平，以及体外培养的野生型和Gata 1（low）DCs对脂多糖的反应。cDC成熟与Gata 1表达的钟形变化相关，Gata 1表达在来自血液的cDC前体中达到峰值。Gata 1（低）突变不影响cDC前体中的Gata 1表达，这些细胞表达HS 2驱动的报告基因，表明Gata 1表达在这些细胞中是HS 2驱动的。相比之下，Gata 1（低）突变降低了成熟cDC中的Gata 1表达，并且这些细胞不表达GFP，表明成熟cDC表达由HS 1驱动的Gata 1。在血液中，Gata 1（低）小鼠中表达CD 40/CD 80的cDC前体数量减少，而野生型小鼠的CD 40（pos）/CD 80（pos）cDC前体表达HS 2-GFP报告基因，表明这些细胞中的Gata 1表达是HS 1和HS 2驱动的。此外，脂多糖诱导的体外野生型DC抗原和辅助分子呈递过程与HS 1乙酰化组蛋白4占据率增加相关，而体外Gata 1（low）cDC对脂多糖无应答，提示HS 1活化是cDC成熟所必需的。这些结果确定了Gata 1调节的动态模式，该模式在与血液中的抗原呈递过程相关的cDC成熟期间从HS 1切换到HS 2依赖性阶段。(C)2010 ISEH -血液学和干细胞学会。爱思唯尔公司出版
Objectives. To identify the regulatory sequences driving Gata1 expression in conventional dendritic cells (cDC).Materials and Methods. The number and expression levels of Gata1, Gata1-target genes and hypersensitive site (HS) 2 (the eosinophil-specific enhancer) driven green fluorescent protein (GFP) reporter of cDCs from mice lacking HS1 (the erythroid/megakaryocytic-specific enhancer, Gata1(low) mutation) and wild-type littermates, as well as the response to lipopolysaccharide of ex vivo generated wild-type and Gata1(low) DCs were investigated.Results. cDC maturation was associated with bell-shaped changes in Gata1 expression that peaked in cDCs precursors from blood. The Gata1(low) mutation did not affect Gata1 expression in cDC precursors and these cells expressed the HS2-driven reporter, indicating that Gata1 expression is HS2-driven in these cells. By contrast, the Gata1(low) mutation reduced Gata1 expression in mature cDCs and these cells did not express GFP, indicating that mature cDCs express Gata1 driven by HS1. In blood, the number of cDC precursors expressing CD40/CD80 was reduced in Gata1(low) mice, while CD40(pos)/CD80(pos) cDC precursors from wild-type mice expressed the HS2-GFP reporter, suggesting that Gata1 expression in these cells is both HS1- and HS2-driven. In addition, the antigen and accessory molecules presentation process induced by lipopolysaccharide in ex vivo generated wild-type DC was associated with increased acetylated histone 4 occupancy of HS1, while ex vivo generated Gata1(low) cDCs failed to respond to lipopolysaccharide, suggesting that HS1 activation is required for cDC maturation.Conclusion. These results identify a dynamic pattern of Gata1 regulation that switches from an HS1 to an HS2-dependent phase during the maturation of cDCs associated with the antigen-presentation process in the blood. (C) 2010 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.