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CAREER: Non-additive control of gene expression by long-range interactions between multiple regulatory elements

职业：通过多个调控元件之间的长程相互作用对基因表达进行非加性控制

基本信息

批准号：
1942471
负责人：
Manu Manu
金额：
$ 86.53万
依托单位：
University of North Dakota Main Campus
依托单位国家：
美国
项目类别：
Continuing Grant
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1942471&HistoricalAwards=false
关键词：
CAREER Non additive control gene

项目摘要

Cells are specialized into different types such as neurons or muscle cells by reading instructions embedded in DNA. These instructions determine which proteins are required for the particular cell type and lead to the production of only those proteins. This project aims to determine the rules by which cells read and execute these instructions. Success of this project advances basic understanding of developmental biology and produces computational tools that are applied to problems ranging from agriculture to human health. In addition to its scientific activities, this project addresses an important challenge in biology education. Specifically, the project is designed to meet future demand for biologists excelling in computational modeling and data analysis in three ways. First, the modeling of biological phenomena is introduced to a broad audience of students that major in biology. Learning modules are developed and deployed in several, hitherto non-quantitative, courses in the biology curriculum. Second, undergraduate students are mentored in research conducted as part of this project. The project also increases the participation of tribal and rural college students in STEM disciplines by hosting the students in the lab during a week-long summer camp as well as during a 6-week long research experience for undergraduate students.The specification of cell fate during development requires the precise modulation of gene expression mediated by DNA sequences called enhancers. In metazoans, most well-studied cell-fate genes are known to be regulated by multiple co-active enhancers, but the rules governing the expression of multi-enhancer loci are not known. This project tests the hypothesis that enhancers interfere with each other over long distances by looping in 3D or modifying the accessibility of chromatin to produce nonlinear or non-additive responses. The studies culminate in the development of a new class of "whole locus" computational models that incorporate 3D chromatin conformation to simulate gene regulation in multi-enhancer loci. The studies utilize the enhancers of Cebpa, a gene necessary for neutrophil development, as models for enhancer interference. The first project aim takes a synthetic biology approach to measure the response of a gene regulated by two enhancers as a function of their strengths. The second project aim profiles 3D contacts between enhancers and promoters and chromatin accessibility to determine whether enhancers interfere with the function of other enhancers by modifying the 3D chromatin conformation or accessibility of the locus. The third project aim integrates looping interactions into sequence-based models of gene regulation to develop a new class of models capable of predicting the gene expression of complex multi-enhancer loci.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

通过读取嵌入 DNA 中的指令，细胞被专门化为不同类型，例如神经元或肌肉细胞。这些指令确定特定细胞类型需要哪些蛋白质，并导致仅生产这些蛋白质。该项目旨在确定细胞读取和执行这些指令的规则。该项目的成功增进了对发育生物学的基本理解，并产生了适用于从农业到人类健康等问题的计算工具。除了科学活动之外，该项目还解决了生物教育中的一个重要挑战。具体来说，该项目旨在通过三种方式满足未来对擅长计算建模和数据分析的生物学家的需求。首先，向生物学专业的广大学生介绍生物现象的建模。学习模块是在生物学课程中的一些迄今为止非定量的课程中开发和部署的。其次，本科生接受作为该项目一部分进行的研究的指导。该项目还通过在实验室举办为期一周的夏令营以及为期 6 周的本科生研究体验，增加了部落和农村大学生对 STEM 学科的参与。发育过程中细胞命运的规范需要对由称为增强子的 DNA 序列介导的基因表达进行精确调节。在后生动物中，已知大多数经过充分研究的细胞命运基因受到多个共活性增强子的调节，但控制多增强子基因座表达的规则尚不清楚。该项目测试了这样的假设：增强子通过 3D 循环或修改染色质的可及性以产生非线性或非加性响应，从而在长距离内相互干扰。这些研究最终开发出了一类新型“全基因座”计算模型，该模型结合了 3D 染色质构象来模拟多增强子基因座的基因调控。这些研究利用 Cebpa（中性粒细胞发育必需的基因）的增强子作为增强子干扰的模型。第一个项目目标采用合成生物学方法来测量由两个增强子调节的基因的反应，作为其强度的函数。第二个项目的目标是分析增强子和启动子之间的 3D 接触以及染色质可及性，以确定增强子是否通过修改 3D 染色质构象或基因座的可及性来干扰其他增强子的功能。第三个项目的目标是将循环相互作用整合到基于序列的基因调控模型中，以开发一类能够预测复杂多增强子位点基因表达的新型模型。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。