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首页> 外文期刊>Molecular and Cellular Biology >Dissection of a Complex Enhancer Element: Maintenance of Keratinocyte Specificity but Loss of Differentiation Specificity
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Dissection of a Complex Enhancer Element: Maintenance of Keratinocyte Specificity but Loss of Differentiation Specificity

机译：复杂增强子的解剖：维持角质形成细胞的特异性，但失去分化特异性

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In this report, we explored the mechanisms underlying keratinocyte-specific and differentiation-specific gene expression in the skin. We have identified five keratinocyte-specific, open chromatin regions that exist within the 6 kb of 5′ upstream regulatory sequence known to faithfully recapitulate the strong endogenous keratin 5 (K5) promoter and/or enhancer activity. One of these, DNase I-hypersensitive site (HSs) 4, was unique in that it acted independently to drive abundant and keratinocyte-specific reporter gene activity in culture and in transgenic mice, despite the fact that it was not essential for K5 enhancer activity. We have identified evolutionarily conserved regulatory elements and a number of their associated proteins that bind to this compact and complex enhancer element. The 125-bp 3′ half of this element (referred to as 4.2) is by far the smallest known strong enhancer element possessing keratinocyte-specific activity in vivo. Interestingly, its activity is restricted to a subset of progeny of K5-expressing cells located within the sebaceous gland. The other half of HSs 4 (termed 4.1) possesses activity to suppress sebocyte-specific expression and induce expression in the channel (inner root sheath) cells surrounding the hair shaft. Our findings lead us to a view of keratinocyte gene expression which is determined by multiple regulatory modules, many of which contain AP-2 and/or Sp1/Sp3 binding sites for enhancing expression in skin epithelium, but which also harbor one or more unique sites for the binding of factors which determine specificity. Through mixing and matching of these modules, additional levels of specificity are obtained, indicating that both transcriptional repressors and activators govern the specificity.
机译：在这份报告中，我们探讨了皮肤中角质形成细胞特异性和分化特异性基因表达的潜在机制。我们已经确定了五个角质形成细胞特异性，开放的染色质区域，这些区域存在于6 kb的5'上游调节序列中，已知该区域忠实地概括了强大的内源性角蛋白5（K5）启动子和/或增强子活性。其中之一是DNase I超敏性位点（HSs）4，其独特之处在于，它在培养物中和转基因小鼠中可独立发挥驱动丰富的角质形成细胞特异的报道基因活性的作用，尽管事实并非如此，这对于K5增强子活性不是必需的。我们已经确定了进化上保守的调控元件，以及与这种紧凑而复杂的增强子元件结合的许多相关蛋白质。该元件的125-bp 3'一半（称为4.2）是迄今为止已知的最小的体内具有角质形成细胞特异性活性的强增强子元件。有趣的是，它的活性仅限于位于皮脂腺内的K5表达细胞的子代。 HSs 4的另一半（称为4.1）具有抑制皮脂细胞特异性表达并诱导发干周围的通道（内根鞘）细胞表达的活性。我们的发现使我们对角质形成细胞基因表达的看法由多个调节模块决定，其中许多模块包含AP-2和/或Sp1 / Sp3结合位点以增强在皮肤上皮细胞中的表达，但也具有一个或多个独特位点用于确定特异性的因素的结合。通过这些模块的混合和匹配，可获得额外的特异性水平，表明转录阻遏物和激活物均控制着特异性。

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