Design principles and dynamic gene control in embryonic development

胚胎发育中的设计原理和动态基因控制

基本信息

批准号：
10662264
负责人：
Bomyi Lim
金额：
$ 38.8万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2025-06-30
项目状态：
未结题

项目摘要

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.

项目概要高通量测序技术的最新进展为其中之一提供了许多见解现代生物学中最基本的问题：基因调控。基因组中的增强子分布，揭示了细胞核中不同的染色体构象，并鉴定然而，基因组中仍然存在与疾病表型高度相关的热点。例如，虽然已经研究了基因表达模式的空间边界。一般来说，我们对增强子和启动子的了解还不太清楚。需要彼此相互作用来产生 mRNA，但尚不清楚它们需要多久发生一次或需要多长时间此外，已知完全去除增强子会废除基因。表达，增强子或增强子-启动子相互作用的中度破坏对发育的影响我相信成像技术的最新进展可以提供同样的功能。通过补充“seq”技术，我在基因调控方面取得了令人兴奋的发现。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，结合实时成像、定量图像分析和数学建模。我建议利用早期果蝇胚胎来研究影响发育的基因控制的三个方面表型：(1) 多种增强子通过减少细胞间的变异性来促进发育稳健性在转录中，（2）保证转录起始的增强子-启动子相互作用的特征， (3) 染色体环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。拟议的研究将提供令人兴奋的新观点。从这项跨学科研究中获得的见解将涉及发育过程中的基因调控领域。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体生理学。