Determining the molecular forces that target transcription factors to DNA in vivo

确定体内转录因子靶向 DNA 的分子力

基本信息

批准号：
8897393
负责人：
Mark D BIGGIN
金额：
$ 19.07万
依托单位：
UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8897393
关键词：
Address Animals Belief Binding Biology Biophysical Process Blastoderm Chromatin Chromatin Modeling Chromatin Structure Collaborations Complex Computer Simulation DNA DNA Binding DNA Sequence DNase I hypersensitive sites sequencing Data Databases Development Drosophila genome Drosophila genus Embryo Gene Expression Profile Generations Genetic Transcription Genome Genomics Hand Hereditary Disease Human Genetics In Vitro Laboratories Learning Measurement Methods Modeling Molecular Nucleosomes Outcome Proteins Publishing Reading Role Series Site Specificity Staging Structure System Testing Thermodynamics Tissues Transgenic Organisms Variant Work abstracting animal tissue embryo cell genome-wide histone modification human disease improved in vivo innovation markov model mathematical model model building novel preference programs protein expression protein protein interaction research study success therapeutic development transcription factor

项目摘要

Project Summary/Abstract One of the greatest challenges in animal biology is to learn how genomic sequence information is read by transcription factors to produce patterns of gene expression within the context of regulatory networks in developing embryos. This Project is part of a broader Program Project that will integrate computational modeling and wet laboratory methods to address this challenge in the belief that only quantitative, predictive mathematical models that have been validated experimentally can provide the rigorous understanding required for modeling transcriptional networks of animals. This Project's contribution to the overall Program will be to develop predictive computational models to understand the molecular mechanisms responsible for targeting transcription factors to DNA in vivo. In Preliminary Studies, we have shown that we can predict in vivo DNA binding with reasonable success using as input only in vitro DNA binding specificity and in vivo chromatin accessibility information and a simple generalized Hidden Markov Model (gHMM). The models are not sufficiently accurate, however. Therefore, we will develop more sophisticated Markov Random Field models that simultaneously consider all of the 32 principal regulatory transcription factors in the Drosophila blastoderm network, a number of ubiquitously expressed transcription factors, nucleosomes, and all of these proteins interactions with DNA and each other. We have divided our modeling into two Aims. The first will extend our current models for chromatin accessibility to determine what drives the genomic distribution of nucleosomes in the embryo, and whether and how nucleosome structure is spatially regulated across the embryo. The second seeks to identify and evaluate the molecular forces that target transcription factors to DNA in vivo. Our models will be tested, refined and validated in a series of transgenic experiments conducted in collaboration with Projects 1 and 2 and the Expression and Database Core. We expect that our models will uncover general principles governing the targeting transcription factors to DNA in vivo that will be applicable to all animal systems. By helping to establishing how to read transcriptional information in animal genomes, this Project will aid both the development of therapeutics for human genetic diseases and the understanding of animal development.

项目摘要/摘要动物生物学中最大的挑战之一是学习如何通过转录因子读取基因组序列信息，以在开发胚胎的调节网络的背景下产生基因表达的模式。该项目是一个更广泛的计划项目的一部分，该项目将集成计算建模和湿实验室方法，以应对这一挑战，以此认为只有定量，预测性经过实验验证的数学模型可以提供建模动物转录网络所需的严格理解。该项目对整个程序的贡献将是开发预测性计算模型，以了解负责转录因子靶向DNA的分子机制。在初步研究中，我们表明，我们可以仅利用AS INPUT在体外DNA结合特异性和体内染色质访问性信息以及简单的体内DNA结合特异性和简单广义隐藏的马尔可夫模型（GHMM）。但是，模型还不够准确。因此，我们将开发更复杂的马尔可夫随机场模型，这些模型同时考虑果蝇胚泡网络中的所有32个主要调节转录因子，许多普遍表达的转录因子，核小体以及所有这些蛋白质与DNA的相互作用。我们将模型分为两个目标。第一个将扩展我们目前的染色质可及性模型，以确定驱动胚胎中核小体基因组分布的是什么，以及核小体结构是否以及如何在整个胚胎上进行空间调节。第二种试图识别和评估靶向转录因子在体内DNA的分子力。我们的模型将在与项目1和2以及表达式和数据库核心合作进行的一系列转基因实验中进行测试，完善和验证。我们预计我们的模型将揭示有关将适用于所有动物系统的DNA的靶向转录因子的一般原则。通过帮助建立如何阅读动物基因组中的转录信息，该项目将有助于为人类遗传疾病的治疗学发展和对动物发育的理解的发展。