The inducible tissue-specific expression of the human IL-3/GM-CSF locus is controlled by a complex array of developmentally regulated enhancers.
The inducible tissue-specific expression of the human IL-3/GM-CSF locus is controlled by a complex array of developmentally regulated enhancers.
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DOI：
10.4049/jimmunol.1201915
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发表时间：
2012-11-01
期刊：
影响因子：
--
通讯作者：
Cockerill PN
中科院分区：
文献类型：
--
作者：
Baxter EW;Mirabella F;Bowers SR;James SR;Bonavita AM;Bertrand E;Strogantsev R;Hawwari A;Bert AG;Gonzalez de Arce A;West AG;Bonifer C;Cockerill PN
紧密相连的人类IL-3和GM-CSF基因受到严格调控，并在激活的T细胞和肥大细胞中表达。在这里，我们使用转基因小鼠来研究该基因座的发育调节，并确定其在体内正确活动所需的DNA元件。由于这两个基因是由依赖于CTCF的绝缘体分开的，而GM-CSF基因主要由它自己的上游增强子调控，所以主要目的是确定正确表达IL-3基因所需的基因座区域。我们最初发现，先前发现的IL-3上游近端的增强子不足以解释IL-3基因在体内的活性。然而，对跨越整个上游IL-3基因间隔区的DNaseI超敏位点(DHSS)的扩展分析表明，存在一个跨越−34至−40kb区域的结构性和诱导性DHSS的复杂簇。这些DHSS的组织特异性反映了IL-3基因的活性，并包括一个位于−37kb的高度可诱导的环孢素A敏感增强子，使IL-3启动子的活性增加了40倍。值得注意的是，包含该区域能够在体内正确地调节T细胞、肥大细胞和髓系祖细胞中IL-3基因的表达。
The closely linked human IL-3 and GM-CSF genes are tightly regulated and are expressed in activated T cells and mast cells. Here we used transgenic mice to study the developmental regulation of this locus and to identify DNA elements required for its correct activity in vivo. Because these two genes are separated by a CTCF-dependent insulator, and the GM-CSF gene is regulated primarily by its own upstream enhancer, the main aim was to identify regions of the locus required for correct IL-3 gene expression. We initially found that the previously identified proximal upstream IL-3 enhancers were insufficient to account for the in vivo activity of the IL-3 gene. However, an extended analysis of DNase I hypersensitive sites (DHSs) spanning the entire upstream IL-3 intergenic region revealed the existence of a complex cluster of both constitutive and inducible DHSs spanning the −34 to −40 kb region. The tissue specificity of these DHSs mirrored the activity of the IL-3 gene, and included a highly inducible CyclosporinA-sensitive enhancer at −37 kb which increased IL-3 promoter activity 40 fold. Significantly, inclusion of this region enabled correct in vivo regulation of IL-3 gene expression in T cells, mast cells and myeloid progenitor cells.
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影响因子：
32.4
作者：
Duncliffe, KN;Bert, AG;Cockerill, PN
通讯作者：
Cockerill, PN
影响因子：
20.3
作者：
Holyoake, TL;Jiang, XY;Eaves, CJ
通讯作者：
Eaves, CJ
Interleukin-3促进小鼠主动脉-性腺-中肾区成血管细胞发育
DOI：
10.3324/haematol.2009.014241
发表时间：
2010-06-01
期刊：
HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
影响因子：
--
作者：
He, Wen-Yan;Lan, Yu;Mao, Ning
通讯作者：
Mao, Ning
影响因子：
1.3
作者：
Cockerill, PN
通讯作者：
Cockerill, PN
影响因子：
5.3
作者：
Johnson, BV;Bert, AG;Cockerill, PN
通讯作者：
Cockerill, PN