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为我们提供了许多关于 现代生物学中最基本的问题：基因调控。这种“SEQ”技术阐明了 基因组中的增强子分布，在细胞核中显示出明显的染色体构象，并鉴定 基因组中与疾病表型高度相关的热点。然而，仍然有 悬而未决的问题。例如，虽然基因表达模式的空间边界已经被研究 广泛地说，基因表达的动力学还没有被很好地理解。我们知道增强剂和促进剂 需要相互作用才能产生信使核糖核酸，但尚不清楚它们多久一次或多长时间需要 相互作用以启动转录。此外，虽然已知完全移除增强子会废除基因 表达，增强子或增强子-启动子相互作用的适度中断对发育的影响 尚未确定其特征。我相信，成像技术的最新进步可以提供同样的 通过补充“序列”技术，在基因调控方面取得令人兴奋的发现。在未来的五年里，我 设想实现对动态基因控制的分子水平的理解，以确保正常发育， 采用实时成像、定量图像分析和数学建模相结合的方法。 利用果蝇早期胚胎，我建议研究影响发育的三个方面的基因控制 表型：(1)多种增强剂通过减少细胞间的变异性来促进发育稳定性 在转录方面，(2)保证转录启动的增强子-启动子相互作用的特征， (3)染色体环区的调控影响增强子-启动子相互作用的错误率 并导致不同的发育表型。拟议的研究将提供令人振奋的新视角 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 与新陈代谢、疾病和其他方面的所有其他基因表达现象相关 人类生理学。

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.