Identification and characterization of a DNase hypersensitive region of the human tyrosinase gene.
Identification and characterization of a DNase hypersensitive region of the human tyrosinase gene.
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DOI：
10.1046/j.1600-0749.2003.00099.x
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发表时间：
2003-12
期刊：
影响因子：
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通讯作者：
J. Fryer;W. Oetting;R. King
中科院分区：
文献类型：
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作者：
J. Fryer;W. Oetting;R. King
酪氨酸酶基因突变产生1型眼皮肤白化病（OCA1）。大多数受影响的个体是具有不同母系和父系突变的复合杂合子，但这些个体中大量假定的酪氨酸酶等位基因在基因的编码区或近端启动子区没有可识别的突变。这表明，基因其他区域的突变，例如从编码序列的直接邻近区域移除的调控区域，可能解释了这些目前无法识别的突变。小鼠酪氨酸酶基因具有远端增强子或基因座控制区（LCR），可提供基因表达的位置无关刺激，而人类基因的同源调控区（HR）可能是其中一些突变的位点。我们报道了人类酪氨酸酶转录起始位点上游9 kb的区域，可能参与了该基因的调控。对该区域的分析显示，dna酶I在细胞谱系特异性模式下过敏，这种模式表明基因的调控区域。当包含该区域的报告载体转染到人类或小鼠黑素细胞细胞系时，该区域也具有显著的增强子功能，消除该区域中与小鼠核心增强子同源的特定序列会使增强子功能消失。我们认为该同源区域包含对人类酪氨酸酶基因调控至关重要的序列，是OCA1突变位置的候选区域。
Mutations of the tyrosinase gene produce oculocutaneous albinism type 1 (OCA1). Most affected individuals are compound heterozygotes with different maternal and paternal mutations, but a substantial number of presumed tyrosinase alleles in these individuals have no identifiable mutation in the coding or proximal promoter region of the gene. This suggests that mutations in other regions of the gene, such as regulatory regions that are removed from the direct proximity of the coding sequence, may account for these currently unidentifiable mutations. The mouse tyrosinase gene has a distal enhancer or locus control region (LCR) that provides position-independent stimulation of gene expression, and a homologous regulatory region (HR) of the human gene could be the site of some of these mutations. We report a region 9 kb upstream of the human tyrosinase transcriptional start site that may be involved in regulation of this gene. Analysis of this region shows DNase I hypersensitivity in a cell lineage-specific pattern, a pattern indicative of regulatory regions of a gene. This region also has significant enhancer function when reporter vectors containing it are transfected into either human or mouse melanocyte cell lines, and elimination of specific sequences with homology to the mouse core enhancer in this region extinguishes the enhancer function. We believe that this region of homology contains sequences critical in the regulation of the human tyrosinase gene and is a candidate for the location of OCA1 mutations.