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

通过阅读DNA中嵌入的指令，细胞被特化成不同类型的细胞，如神经元或肌肉细胞。这些指令决定了特定细胞类型所需的蛋白质，并导致只产生这些蛋白质。该项目旨在确定单元格读取和执行这些指令所依据的规则。该项目的成功促进了对发育生物学的基本理解，并产生了应用于从农业到人类健康等一系列问题的计算工具。除了它的科学活动，这个项目还解决了生物教育中的一个重要挑战。具体地说，该项目旨在满足未来对在三个方面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。学习模块被开发和部署在生物课程中的几个迄今非定量的课程中。其次，作为该项目的一部分，本科生在研究中得到指导。该项目还通过在为期一周的夏令营和为期六周的本科生研究体验期间在实验室接待学生，增加部落和农村大学生对STEM学科的参与。在发育过程中对细胞命运的指定需要通过称为增强子的DNA序列介导的基因表达的精确调控。在后生动物中，大多数被充分研究的细胞命运基因都受到多个共同作用的增强子的调控，但控制多个增强子基因表达的规则尚不清楚。这个项目测试了一种假说，即增强剂通过在3D中循环或改变染色质的可及性来产生非线性或非加性反应，从而在长距离内相互干扰。这些研究的最终结果是开发了一类新的“全基因座”计算模型，该模型结合了3D染色质构象来模拟多个增强子基因座的基因调控。这些研究利用CEBPA的增强子作为增强子干扰的模型，CEBPA是中性粒细胞发育所必需的基因。第一个项目Aim采用了一种合成生物学的方法来测量受两个增强子调控的基因的反应，作为它们强度的函数。第二个项目Aim描述了增强子和启动子之间的3D接触和染色质可及性，以确定增强子是否通过改变基因座的3D染色质构象或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集成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区域的基因表达的新模型。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.