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首页> 外文期刊>Molecular and Cellular Biology >Identification of Distal cis-Regulatory Elements at Mouse Mitoferrin Loci Using Zebrafish Transgenesis
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Identification of Distal cis-Regulatory Elements at Mouse Mitoferrin Loci Using Zebrafish Transgenesis

机译：使用斑马鱼转基因鉴定小鼠线粒体铁蛋白基因座远端顺式调控元件。

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Mitoferrin 1 (Mfrn1; Slc25a37) and mitoferrin 2 (Mfrn2; Slc25a28) function as essential mitochondrial iron importers for heme and Fe/S cluster biogenesis. A genetic deficiency of Mfrn1 results in a profound hypochromic anemia in vertebrate species. To map the cis-regulatory modules (CRMs) that control expression of the Mfrn genes, we utilized genome-wide chromatin immunoprecipitation (ChIP) datasets for the major erythroid transcription factor GATA-1. We identified the CRMs that faithfully drive the expression of Mfrn1 during blood and heart development and Mfrn2 ubiquitously. Through in vivo analyses of the Mfrn-CRMs in zebrafish and mouse, we demonstrate their functional and evolutionary conservation. Using knockdowns with morpholinos and cell sorting analysis in transgenic zebrafish embryos, we show that GATA-1 directly regulates the expression of Mfrn1. Mutagenesis of individual GATA-1 binding cis elements (GBE) demonstrated that at least two of the three GBE within this CRM are functionally required for GATA-mediated transcription of Mfrn1. Furthermore, ChIP assays demonstrate switching from GATA-2 to GATA-1 at these elements during erythroid maturation. Our results provide new insights into the genetic regulation of mitochondrial function and iron homeostasis and, more generally, illustrate the utility of genome-wide ChIP analysis combined with zebrafish transgenesis for identifying long-range transcriptional enhancers that regulate tissue development.
机译：线粒体铁蛋白1（Mfrn1; Slc25a37）和线粒体铁蛋白2（Mfrn2; Slc25a28）作为血红素和Fe / S团簇生物发生的线粒体铁必需输入物。 Mfrn1的遗传缺陷导致脊椎动物物种发生严重的低色素性贫血。为了绘制控制Mfrn基因表达的 cis 调控模块（CRM），我们利用了全基因组染色质免疫沉淀（ChIP）数据集作为主要的类红细胞转录因子GATA-1。我们确定了在血液和心脏发育过程中忠实地驱动Mfrn1和Mfrn2表达的CRM。通过对斑马鱼和小鼠中的Mfrn-CRMs的体内分析，我们证明了它们的功能和进化保守性。使用转基因斑马鱼胚胎中的吗啉代敲低和细胞分选分析，我们表明，GATA-1直接调节Mfrn1的表达。单个GATA-1结合 cis 元素（GBE）的诱变表明，此CRM内三个GBE中的至少两个是GATA介导的Mfrn1转录功能所需的。此外，ChIP分析表明在类红细胞成熟过程中这些元件从GATA-2转换为GATA-1。我们的结果为线粒体功能和铁稳态的遗传调控提供了新的见解，并且更普遍地说明了全基因组ChIP分析与斑马鱼转基因相结合用于识别调节组织发育的远程转录增强子的实用性。

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