An integrated Holo-Enhancer Unit Defines Tissue and Gene Specificity of the Fgf8 Regulatory Landscape
An integrated Holo-Enhancer Unit Defines Tissue and Gene Specificity of the Fgf8 Regulatory Landscape
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DOI：
10.1016/j.devcel.2013.01.025
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发表时间：
2013-03-11
影响因子：
11.8
通讯作者：
Spitz, Francois
中科院分区：
文献类型：
--
作者：
Marinic, Mirna;Aktas, Tugce;Spitz, Francois
Fgf8编码一个关键的信号因子，它的精确调控对胚胎模式至关重要。在这里，我们确定了在哺乳动物胚胎发育过程中控制Fgf8表达的调控模块。这些增强子在220kb的大区域中夹杂着无关的基因，但它们只作用于Fgf8。有趣的是，该区域还包含其他未转化为基因表达的真正的增强子活动。利用基因组工程策略，我们证明了这些多个不同的调控模块作为一个连贯的单位，并根据它们的位置而不是它们的启动子序列来影响基因。这些发现突出了一个基因座的结构如何调节它所包含的调控元件的自主内在活动，并有助于它们的组织和靶标特异性。我们讨论了这些调控系统对基因表达进化和人类基因组结构变异的影响的影响。
Fgf8 encodes a key signaling factor, and its precise regulation is essential for embryo patterning. Here, we identified the regulatory modules that control Fgf8 expression during mammalian embryogenesis. These enhancers are interspersed with unrelated genes along a large region of 220 kb; yet they act on Fgf8 only. Intriguingly, this region also contains additional genuine enhancer activities that are not transformed into gene expression. Using genomic engineering strategies, we showed that these multiple and distinct regulatory modules act as a coherent unit and influence genes depending on their position rather than on their promoter sequence. These findings highlight how the structure of a locus regulates the autonomous intrinsic activities of the regulatory elements it contains and contributes to their tissue and target specificities. We discuss the implications of such regulatory systems regarding the evolution of gene expression and the impact of human genomic structural variations.