Department of Biology, Center for Developmental Genetics, New York University, New York, New York, USA.
PLoS Genet. 2011 Oct;7(10):e1002339. doi: 10.1371/journal.pgen.1002339. Epub 2011 Oct 20.
In past years, much attention has focused on the gene networks that regulate early developmental processes, but less attention has been paid to how multiple networks and processes are temporally coordinated. Recently the discovery of the transcriptional activator Zelda (Zld), which binds to CAGGTAG and related sequences present in the enhancers of many early-activated genes in Drosophila, hinted at a mechanism for how batteries of genes could be simultaneously activated. Here we use genome-wide binding and expression assays to identify Zld target genes in the early embryo with the goal of unraveling the gene circuitry regulated by Zld. We found that Zld binds to genes involved in early developmental processes such as cellularization, sex determination, neurogenesis, and pattern formation. In the absence of Zld, many target genes failed to be activated, while others, particularly the patterning genes, exhibited delayed transcriptional activation, some of which also showed weak and/or sporadic expression. These effects disrupted the normal sequence of patterning-gene interactions and resulted in highly altered spatial expression patterns, demonstrating the significance of a timing mechanism in early development. In addition, we observed prevalent overlap between Zld-bound regions and genomic "hotspot" regions, which are bound by many developmental transcription factors, especially the patterning factors. This, along with the finding that the most over-represented motif in hotspots, CAGGTA, is the Zld binding site, implicates Zld in promoting hotspot formation. We propose that Zld promotes timely and robust transcriptional activation of early-gene networks so that developmental events are coordinated and cell fates are established properly in the cellular blastoderm embryo.
在过去的几年中，人们非常关注调控早期发育过程的基因网络，但对多个网络和过程如何进行时间协调的关注较少。最近，转录激活因子 Zelda（Zld）的发现暗示了一种机制，即多个基因簇如何能够同时被激活。Zld 结合到果蝇中许多早期激活基因的增强子中的 CAGGTAG 和相关序列上，提示了一种机制，说明多个网络和过程如何进行时间协调。本文中，我们使用全基因组结合和表达分析来鉴定早期胚胎中的 Zld 靶基因，旨在揭示受 Zld 调控的基因电路。我们发现，Zld 结合到参与细胞化、性别决定、神经发生和模式形成等早期发育过程的基因。在没有 Zld 的情况下，许多靶基因无法被激活，而其他基因，特别是那些模式形成基因，表现出转录激活延迟，其中一些基因也表现出微弱和/或零星的表达。这些影响打乱了模式形成基因相互作用的正常顺序，并导致高度改变的空间表达模式，证明了时间机制在早期发育中的重要性。此外，我们观察到 Zld 结合区域与基因组“热点”区域之间存在普遍重叠，这些区域被许多发育转录因子结合，特别是模式形成因子。这一点，以及热点中最常见的基序 CAGGTA 是 Zld 结合位点的发现，表明 Zld 参与了热点的形成。我们提出，Zld 促进早期基因网络的及时和强大的转录激活，从而协调发育事件，并在细胞胚层胚胎中正确建立细胞命运。
