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

通过解读嵌入DNA中的指令，细胞可以分化成不同的类型，如神经元或肌肉细胞。这些指令决定了特定细胞类型需要哪些蛋白质，并导致只生产这些蛋白质。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各种问题的计算工具。除了科学活动外，该项目还解决了生物教育中的一个重要挑战。具体而言，该项目旨在满足未来对在计算建模和数据分析方面表现出色的生物学家的需求。首先，将生物现象的建模介绍给生物学专业的广大学生。学习模块被开发和部署在生物课程的几个迄今为止非定量的课程中。第二，本科生在作为该项目的一部分进行的研究中得到指导。该项目还通过在实验室举办为期一周的夏令营和为期六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。在发育过程中，细胞命运的规范需要被称为增强子的DNA序列介导的基因表达的精确调节。在后生动物中，大多数研究充分的细胞命运基因已知由多个协同活性增强子调节，但控制多增强子位点表达的规则尚不清楚。该项目测试了一个假设，即增强子通过在3D中循环或修改染色质的可及性来产生非线性或非加性反应，从而在长距离上相互干扰。这些研究最终发展了一类新的“全基因座”计算模型，该模型结合了三维染色质构象来模拟多增强子基因座中的基因调控。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。第一个项目的目标是采用合成生物学的方法来测量由两个增强子调控的基因的反应，作为它们强度的函数。第二个项目旨在描述增强子和启动子之间的三维接触以及染色质可及性，以确定增强子是否通过改变染色质的三维构象或位点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模型。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值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.