Changes in the enhancer landscape during early placental development uncover a trophoblast invasion gene-enhancer network.
Changes in the enhancer landscape during early placental development uncover a trophoblast invasion gene-enhancer network.
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DOI：
10.1016/j.placenta.2015.11.001
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发表时间：
2016-01
期刊：
影响因子：
3.8
通讯作者：
Bejerano G
中科院分区：
文献类型：
--
作者：
Tuteja G;Chung T;Bejerano G
在胎盘发育早期，滋养层细胞的侵入在母亲和胎儿之间建立了足够的血流。然而，很少有人知道的顺式调控机制，这一重要的过程。我们的目的是确定在滋养层侵袭过程中活跃的增强子元件，并建立滋养层侵袭基因-增强子网络。我们在小鼠胎盘发育早期的两个时间点进行了增强子相关标记（H3 k27 Ac）的ChIP-Seq。一个时间点是侵袭处于其高峰（e7.5），另一个时间点是不久之后（e9.5）。我们使用计算分析，以确定假定的增强子，以及它们内的转录因子结合位点，这是特定的时间点的滋养层入侵。我们比较了e7.5和e9.5的读段谱，以鉴定1，977个e7.5特异性增强子。在e7.5特异性增强子的一个子集中，我们发现了一个与细胞迁移相关的调控密码，由三个转录因子基序组成：AP 1，Ets和Tcfap 2。为了验证结合这些基序的转录因子的差异表达，我们在相同的背景下进行了RNA-Seq。最后，我们将这些数据与公开的蛋白质-蛋白质相互作用数据相结合，构建了一个滋养层侵袭基因-增强子网络。我们产生的数据和我们进行的分析，提高了我们的滋养层入侵的调控机制的理解，通过提示细胞迁移基因的增强子中存在的转录密码。此外，我们构建的网络突出了可能对滋养层侵袭至关重要的新候选基因。
Trophoblast invasion establishes adequate blood flow between mother and fetus in early placental development. However, little is known about the cis-regulatory mechanisms underlying this important process. We aimed to identify enhancer elements that are active during trophoblast invasion, and build a trophoblast invasion gene-enhancer network. We carried out ChIP-Seq for an enhancer-associated mark (H3k27Ac) at two time points during early placental development in mouse. One time point where invasion is at its peak (e7.5) and another time point shortly afterwards (e9.5). We use computational analysis to identify putative enhancers, as well as the transcription factor binding sites within them, that are specific to the time point of trophoblast invasion. We compared read profiles at e7.5 and e9.5 to identify 1,977 e7.5-specific enhancers. Within a subset of e7.5-specific enhancers, we discovered a cell migration associated regulatory code, consisting of three transcription factor motifs: AP1, Ets, and Tcfap2. To validate differential expression of the transcription factors that bind these motifs, we performed RNA-Seq in the same context. Finally, we integrated these data with publicly available protein-protein interaction data and constructed a trophoblast invasion gene-enhancer network. The data we generated and analysis we carried out improves our understanding of the regulatory mechanisms of trophoblast invasion, by suggesting a transcriptional code exists in the enhancers of cell migration genes. Furthermore, the network we constructed highlights novel candidate genes that may be critical for trophoblast invasion.