Design principles and dynamic gene control in embryonic development

项目摘要 高通量测序技术的最新进展已经提供了许多对其中一个基因的深入了解。 现代生物学中最基本的问题：基因调控。这种“seq”技术已经阐明了 增强子在基因组中的分布，揭示了细胞核中不同的染色体构象，并确定了 基因组内与疾病表型高度相关的热点。然而， 没有答案的问题例如，虽然已经研究了基因表达模式的空间边界， 基因表达的动力学还没有被广泛地理解。我们知道增强子和启动子 需要相互作用以产生mRNA，但尚不清楚它们需要多久或多久才能相互作用。 相互作用以启动转录。此外，虽然已知完全去除增强子可以消除基因， 表达，增强子或增强子-启动子相互作用的适度破坏对发育的影响 还有待鉴定我相信最近成像技术的进步同样可以提供 通过补充“seq”技术在基因调控方面的令人兴奋的发现。在接下来的五年里，我 设想实现对动态基因控制的分子水平理解，以确保正常发育， 使用实时成像、定量图像分析和数学建模的组合。 利用果蝇早期胚胎，我建议研究影响发育的基因控制的三个方面， 表型：（1）通过减少细胞间变异性促进发育稳健性的多种增强子 在转录中，（2）保证转录起始的增强子-启动子相互作用的特征， 以及（3）染色体环结构域的调节影响增强子-启动子相互作用的错误率 并导致可变的发育表型。这项拟议中的研究将提供令人兴奋的新视角 在发育过程中的基因调控领域。从这项跨学科研究中获得的见解将 与所有其他基因表达现象相关，这些现象是代谢、疾病和其他方面的基础。 人体生理学

Project Summary Recent advancements in high-throughput sequencing techniques have provided many insights into one of the most fundamental questions in modern biology: gene regulation. Such “seq” techniques have elucidated enhancer distributions in the genome, revealed distinct chromosome conformation in a nucleus, and identified hotspots within the genome that are highly associated with disease phenotypes. And yet, there remain unanswered questions. For example, while spatial boundary of gene expression pattern has been studied extensively, the kinetics of gene expression is not as well understood. We know that enhancer and promoter need to interact with each other to produce mRNA, but it is not clear how often, or how long they need to interact to initiate transcription. Moreover, while complete removal of an enhancer is known to abolish gene expression, the effect of moderate disruptions in enhancer or enhancer-promoter interactions on development is yet to be characterized. I believe that recent advancement in imaging techniques can provide equally exciting discoveries in gene regulation by complementing the “seq” techniques. In the next five years, I envision achieving molecular-level understanding of dynamic gene control that ensures normal development, using combination of live imaging, quantitative image analysis, and mathematical modeling. Using early Drosophila embryo, I propose to study three aspects of gene control that affect developmental phenotypes: (1) multiple enhancers contributing to developmental robustness by reducing cell-to-cell variability in transcription, (2) characteristics of enhancer-promoter interactions that guarantee transcriptional initiation, and (3) modulations in chromosomal loop domain affecting the error-rate of enhancer-promoter interactions and leading to variable developmental phenotypes. The proposed study will provide exciting new perspectives on the field of gene regulation during development. The insights obtained from this interdisciplinary study will be relevant to all other gene expression phenomena underlying metabolism, disease, and other aspects of human physiology.