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首页> 外文期刊>Pigment cell research >Gene expression profiling of cultured human NF1 heterozygous (NF1(+/-)) melanocytes reveals downregulation of a transcriptional cis-regulatory network mediating activation of the melanocyte-specific dopachrome tautomerase (DCT) gene
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Gene expression profiling of cultured human NF1 heterozygous (NF1(+/-)) melanocytes reveals downregulation of a transcriptional cis-regulatory network mediating activation of the melanocyte-specific dopachrome tautomerase (DCT) gene

机译：培养的人类NF1杂合（NF1（+/-））黑素细胞的基因表达谱揭示调解介导黑素细胞特异性多巴色素互变异构酶（DCT）基因激活的转录顺式调控网络的下调。

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One of the major primary features of the neurocutaneous genetic disorder Neurofibromatosis type 1 are the hyperpigmentary cafe-au-lait macules where disregulation of melanocyte biology is supposed to play a key etiopathogenic role. To gain better insight into the possible role of the tumor suppressor gene NF1, a transcriptomic microarray analysis was performed on human NF1 heterozygous (NF1(+/-)) melanocytes of a Neurofibromatosis type 1 patient and NF1 wild type (NF1(+/+)) melanocytes of a healthy control patient, both cultured from normally pigmented skin and hyperpigmented lesional cafe-au-lait skin. From the magnitude of gene effects, we found that gene expression was affected most strongly by genotype and less so by lesional type. A total of 137 genes had a significant twofold or more up- (72) or downregulated (65) expression in NF1(+/-) melanocytes compared with NF1(+/+) melanocytes. Melanocytes cultured from hyperpigmented cafe-au-lait skin showed 37 upregulated genes whereas only 14 were downregulated compared with normal skin melanocytes. In addition, significant genotype xlesional type interactions were observed for 465 genes. Differentially expressed genes were mainly involved in regulating cell proliferation and cell adhesion. A high number of transcription factor genes, among which a specific subset important in melanocyte lineage development, were downregulated in the cis-regulatory network governing the activation of the melanocyte-specific dopachrome tautomerase (DCT) gene. Although the results presented have been obtained with a restricted number of patients (one NF1 patient and one control) and using cDNA microarrays that may limit their interpretation, the data nevertheless addresses for the first time the effect of a heterozygous NF1 gene on the expression of the human melanocyte transcriptome and has generated several interesting candidate genes helpful in elucidating the etiopathology of cafe-au-lait macules in NF1 patients.
机译：神经皮肤遗传疾病1型神经纤维瘤病的主要主要特征之一是色素沉着的网状斑丘疹，其中黑素细胞生物学的失调可能起着关键的病因作用。为了更好地了解肿瘤抑制基因NF1的可能作用，对神经纤维瘤病1型患者和野生型NF1（NF1（+ / +）的人类NF1杂合（NF1（+/-））黑色素细胞进行了转录组微阵列分析））健康对照患者的黑素细胞，均从正常色素性皮肤和色素沉着的病灶咖啡色皮肤中培养。从基因效应的程度，我们发现基因表达受基因型影响最大，而受病灶类型影响较小。与NF1（+ / +）黑色素细胞相比，总共137个基因在NF1（+/-）黑色素细胞中具有显着两倍以上的上调（72）或下调（65）表达。与正常皮肤黑素细胞相比，从色素沉着的cafe-au-lait皮肤培养的黑素细胞显示37个上调的基因，而只有14个被下调。另外，对于465个基因观察到显着的基因型xlesional类型相互作用。差异表达的基因主要参与调节细胞增殖和细胞粘附。大量的转录因子基因，其中一个在黑素细胞谱系发育中重要的特定子集，在控制黑素细胞特异性多巴色素互变异构酶（DCT）基因激活的顺式调控网络中被下调。尽管仅有限数量的患者（一个NF1患者和一个对照）获得了上述结果，但使用了可能会限制其解释的cDNA微阵列，但该数据还是首次解决了杂合性NF1基因对HIF1基因表达的影响。人类黑素细胞转录组，并产生了一些有趣的候选基因，有助于阐明NF1患者网状黄斑的病因。

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