Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA.
Joseph Henry Laboratories of Physics, Princeton University, Princeton, NJ, USA.
Nature. 2022 May;605(7911):754-760. doi: 10.1038/s41586-022-04680-7. Epub 2022 May 4.
The prevailing view of metazoan gene regulation is that individual genes are independently regulated by their own dedicated sets of transcriptional enhancers. Past studies have reported long-range gene-gene associations, but their functional importance in regulating transcription remains unclear. Here we used quantitative single-cell live imaging methods to provide a demonstration of co-dependent transcriptional dynamics of genes separated by large genomic distances in living Drosophila embryos. We find extensive physical and functional associations of distant paralogous genes, including co-regulation by shared enhancers and co-transcriptional initiation over distances of nearly 250 kilobases. Regulatory interconnectivity depends on promoter-proximal tethering elements, and perturbations in these elements uncouple transcription and alter the bursting dynamics of distant genes, suggesting a role of genome topology in the formation and stability of co-transcriptional hubs. Transcriptional coupling is detected throughout the fly genome and encompasses a broad spectrum of conserved developmental processes, suggesting a general strategy for long-range integration of gene activity.
后生动物基因调控的主流观点认为，单个基因是由其自身专用的转录增强子集独立调控的。过去的研究已经报道了长程基因-基因关联，但它们在调控转录中的功能重要性仍不清楚。在这里，我们使用定量单细胞活细胞成像方法，在活体果蝇胚胎中提供了基因间远距离基因的转录动力学依赖关系的实例。我们发现，远源的基因在物理和功能上存在广泛的关联，包括通过共享增强子的共同调控和近 250kb 距离上的共转录起始。这种调控的互连接取决于启动子近端的连接元件，而这些元件的扰动会使转录解耦并改变远源基因的爆发动力学，这表明基因组拓扑结构在转录共表达中心的形成和稳定性中发挥了作用。在整个果蝇基因组中都检测到了转录偶联，并且包含了广泛的保守发育过程，这表明了长程基因活性整合的一般策略。
