Identification of regulatory elements in the Isl1 gene locus.
Identification of regulatory elements in the Isl1 gene locus.
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DOI：
10.1387/ijdb.082819ck
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Salbaum JM
中科院分区：
文献类型：
--
作者：
Kappen C;Salbaum JM
Isl 1是一种LIM/同源结构域转录因子，在心脏、神经系统和胰腺的发育中起关键作用。Isl 1的缺陷和错误表达都会导致严重的发育缺陷，这表明在发育过程中正确调节Isl 1基因表达的重要性。为了了解在胚胎发生和组织分化过程中控制Isl 1表达的机制，我们使用一种新型的双报告基因载体，通过体外和体内报告基因检测，对Isl 1基因座中的基因调控元件进行了筛选。我们确定了从Isl 1基因位点，赋予胰腺细胞系在体外转录活性的区域。使用转基因小鼠，我们还发现了一种增强子，对发育中的心脏以及内脏和后中胚层具有体内特异性。我们的研究结果进一步表明，Foxo 1以及Gata 4有助于这种增强子在发育胚胎中的活性。我们的结论是，Isl 1基因的表达控制模块化的方式由几个元素具有不同的功能。在中胚层起源的几种组织中的胚胎Isl 1表达由位于基因下游3- 6 kb的特异性增强子驱动。
Isl1 is a LIM/homeodomain transcription factor with critical roles for the development of the heart, the nervous system and the pancreas. Both deficiency and mis-expression of Isl1 cause profound developmental defects, demonstrating the importance of proper regulation of Isl1 gene expression during development. In order to understand the mechanisms that control Isl1 expression during embryogenesis and in tissue differentiation, we initiated a screen for gene regulatory elements in the Isl1 locus using a novel dual reporter gene vector that allows screens of large genomic regions through reporter gene assays in vitro and in vivo. We identified regions from the Isl1 gene locus that confer transcriptional activity in pancreatic cell lines in vitro. Using transgenic mice, we furthermore discovered an enhancer with in vivo specificity for the developing heart, as well as visceral and posterior mesoderm. Our findings further suggest that Foxo1 as well as Gata4 contribute to the activity of this enhancer in the developing embryo. We conclude that Isl1 gene expression is controlled in modular fashion by several elements with distinct functionality. Embryonic Isl1 expression in several tissues of mesodermal origin is driven by a specific enhancer that is located 3-6kb downstream of the gene.
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