Developmental Biology Unit, EMBL, Meyerhofstrasse 1, Heidelberg 69117, Germany.
Dev Cell. 2013 Mar 11;24(5):530-42. doi: 10.1016/j.devcel.2013.01.025. Epub 2013 Feb 28.
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.
Fgf8 编码一种关键的信号因子，其精确调节对于胚胎模式形成至关重要。在这里，我们确定了控制哺乳动物胚胎发生过程中 Fgf8 表达的调节模块。这些增强子沿着 220kb 的大片区域与不相关的基因交错排列; 然而，它们只作用于 Fgf8。有趣的是，该区域还包含其他不转化为基因表达的真正增强子活性。使用基因组工程策略，我们表明这些多个和不同的调节模块作为一个连贯的单元起作用，并根据它们的位置而不是启动子序列来影响基因。这些发现强调了基因座的结构如何调节其包含的调节元件的自主内在活性，并有助于它们的组织和靶特异性。我们讨论了这种调节系统对基因表达进化的影响以及人类基因组结构变异的影响。
