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.

通过阅读嵌入DNA中的指令，细胞专用于不同类型，例如神经元或肌肉细胞。这些指令确定了特定细胞类型所需的哪些蛋白质，并仅导致这些蛋白质的产生。该项目旨在确定单元格读取和执行这些指令的规则。该项目的成功促进了对发育生物学的基本了解，并生产出用于从农业到人类健康等问题的计算工具。除了其科学活动外，该项目还解决了生物学教育中的重要挑战。具体而言，该项目旨在满足对生物学家的未来需求，以三种方式在计算建模和数据分析方面出色。首先，将生物现象的建模引入了生物学专业的广泛学生。学习模块是在生物学课程中开发和部署的几个非量化课程中的。其次，本科生的研究是该项目的一部分进行的研究。该项目还通过在为期一周的夏季营地以及为期6周的本科生研究经验中托管实验室的学生，增加了部落和农村大学生在STEM学科中的参与。开发过程中细胞命运的规格需要通过DNA序列介导的DNA序列的精确调节。在后生动物中，已知大多数研究的细胞效果基因受多个共同活性增强子的调节，但是尚不清楚管理多增强基因座表达的规则。该项目检验了以下假设，即通过在3D中循环或修改染色质以产生非线性或非腺反应的可访问性来增强彼此之间相互干扰。研究最终在开发新的“整个基因座”计算模型的开发中，这些模型结合了3D染色质构象以模拟多增强基因座中的基因调节。这些研究利用Cebpa的增强子，Cebpa是中性粒细胞发育所必需的基因，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衡量由两个增强子调节的基因的反应，其优势的函数。第二个项目目标剖面3D接触增强剂和启动子之间以及染色质的可及性，以确定增强子是否通过修改3D染色质构象或可及性的可及性来干扰其他增强剂的功能。第三个项目的目标将循环相互作用集成到基于序列的基因调节模型中，以开发一种新的模型，能够预测复杂的多增强剂基因座的基因表达。该奖项反映了NSF的法定任务，并被认为是值得通过基金会的知识分子和更广泛影响的审查标准来通过评估来通过评估来支持的。