Enhance human ENCODE by function comparisons to mouse

通过与小鼠的功能比较来增强人类 ENCODE

基本信息

批准号：
7852369
负责人：
ROSS C HARDISON
金额：
$ 75万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-26 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7852369
关键词：
Adopted BFU-E Base Sequence Binding Binding Sites Biochemical Biochemical Markers Biological Assay Biological Process Cell Line Cell model Cells Chromatin Structure Chromosomes Classification Collaborations Complement Complex Correlative Study DNA DNA Sequence DNA-Protein Interaction Data Deoxyribonucleases Development Developmental Biology Diabetes Mellitus Disease Disease susceptibility Elements Enhancers Erythroblasts Erythropoiesis Event Evolution Frequencies Future GATA1 gene Gene Expression Genes Genetic Genome Goals Harvest Heart Diseases Human Human Cell Line Human Genome Human Genome Project Indium Individual Institution Investigation Lead Light Location Lymphocyte Lymphoid Machine Learning Malignant Neoplasms Mammals Maps Molecular Molecular Conformation Molecular Evolution Molecular Genetics Mouse Cell Line Mus Muscle Cells Myelogenous National Human Genome Research Institute Nuclear Persons Phase Phylogenetic Analysis Predisposition Prevention Problem Solving Process Quality Control Request for Applications Research Research Personnel Sequence Analysis Site Sorting - Cell Movement Staging Stimulus System Technology Time Study Transcript Transcription Initiation Site Transcriptional Regulation Variant Work base cell type comparative data mining effective therapy embryonic stem cell genome sequencing genome-wide high standard histone modification human GATA1 protein human data human disease improved insight mouse genome novel pathogen promoter public health relevance response restoration transcription factor

Adopted BFU-E Base Sequence Binding Binding Sites Biochemical Biochemical Markers Biological Assay Biological Process Cell Line Cell model Cells Chromatin Structure Chromosomes Classification Collaborations Complement Complex Correlative Study DNA DNA Sequence DNA-Protein Interaction Data Deoxyribonucleases Development Developmental Biology Diabetes Mellitus Disease Disease susceptibility Elements Enhancers Erythroblasts Erythropoiesis Event Evolution Frequencies Future GATA1 gene Gene Expression Genes Genetic Genome Goals Harvest Heart Diseases Human Human Cell Line Human Genome Human Genome Project Indium Individual Institution Investigation Lead Light Location Lymphocyte Lymphoid Machine Learning Malignant Neoplasms Mammals Maps Molecular Molecular Conformation Molecular Evolution Molecular Genetics Mouse Cell Line Mus Muscle Cells Myelogenous National Human Genome Research Institute Nuclear Persons Phase Phylogenetic Analysis Predisposition Prevention Problem Solving Process Quality Control Request for Applications Research Research Personnel Sequence Analysis Site Sorting - Cell Movement Staging Stimulus System Technology Time Study Transcript Transcription Initiation Site Transcriptional Regulation Variant Work base cell type comparative data mining effective therapy embryonic stem cell genome sequencing genome-wide high standard histone modification human GATA1 protein human data human disease improved insight mouse genome novel pathogen promoter public health relevance response restoration transcription factor

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项目摘要

DESCRIPTION (provided by applicant): Our goal is to discover and use relationships between mouse and human regulatory genomes to advance the ENCODE Project in its effort to map all functional elements in the human genome. Our comparative approach aims to uncover principles and solve problems that are proving difficult by studying the human genome alone. ENCODE is vigorously mapping hundreds of function-associated biochemical markers in selected cell lines, resulting already in tens of millions of reproducible biochemical features. Some observed protein:DNA interactions find and refine known transcriptional enhancers, promoters, silencers, together with associated chromatin structure, as was anticipated. But substantial questions arise as to how many of the myriad biochemical events are functional, what those functions are, which gene or genes are meaningful targets, etc. To highlight and sort functionally important biochemical marks from others, we will systematically identify the molecular events retained by both mouse and human since they diverged. We will then analyze how conservation of biochemical features relates to conservation of DNA sequence and conservation of regulated gene expression. By using the mouse, we can leverage decades of molecular genetics and manipulated mouse genomes that do not exist in any other mammal. In Aim 1 we execute genome-wide assays for biochemical signatures of functional DNA sequences in a few specific mouse cell types. By using well-studied mouse lines and cell states, we can interpret results in light of previously validated elements and in light of ENCODE human results. We will use ENCODE standards for high throughput, sequence-based assays to determine gene expression, DNase hypersensitive sites, histone modifications and selected transcription factor occupancy in seven mouse cell types. The eight selected features are the most informative ones for function, and thus most useful for comparison with human data. In Aim 2, we apply a genome-wide implementation of chromosome conformation capture to map the interactions between transcription factor binding sites and their responsive genes in two cell types. These results will be compared to those from an ENCODE developmental project. Comparative analysis in Aim 3 will insure that the impact of the data we produce will go beyond the individual mouse cell systems per se. To do this we have organized a collaboration of investigators at multiple institutions, in which each group is expert in one or more critical aspects. Our data, made public and accessible via ENCODE, will fuel and accelerate many future studies after the 2-yr stimulus both in and beyond ENCODE. This responds to NHGRI request for applications on "Enhancement of the value of the human ENCODE Project by conducting a parallel effort on the mouse genome." The proposed work will improve the maps of biologically functional DNA sequences in humans, which in turn will help explain how variants in human genome sequences could be associated with human diseases, leading to candidates for novel avenues for effective therapy and prevention. PUBLIC HEALTH RELEVANCE: Every person differs in his or her response to pathogens and in the likelihood that they will suffer from complex diseases such as cancer, heart disease or diabetes. Individual susceptibility to disease is determined in part by genetics, and we can map with high precision the locations of DNA variants associated with disease susceptibility. In order to understand how these variants contribute to disease susceptibility, we need to identify the biological functions of all DNA sequences; the proposed work will help us map these functional DNA sequences.

描述（由申请人提供）：我们的目标是发现和使用人与人类调节基因组之间的关系，以推进编码项目，以绘制人类基因组中的所有功能元素。我们的比较方法旨在发现原则和解决问题，这些问题仅通过研究人类基因组而被证明是困难的。编码在选定的细胞系中大力绘制了数百个与功能相关的生化标记，这已经产生了数千万可再现的生化特征。一些观察到的蛋白质：DNA相互作用发现并完善已知的转录增强子，启动子，消音器以及相关的染色质结构，如预期的。但是，关于有多少千种生化事件起作用，这些功能是什么，哪些基因或基因是有意义的靶标，等等，以突出和分类他人的功能重要重要的生化标记，我们将系统地识别小鼠和人的分子事件。然后，我们将分析生化特征的保护如何与DNA序列的保存和调节基因表达的保存有关。通过使用小鼠，我们可以利用在任何其他哺乳动物中都不存在的数十年的分子遗传学和操纵小鼠基因组。在AIM 1中，我们对几种特定小鼠细胞类型的功能性DNA序列的生化特征执行全基因组测定法。通过使用良好的小鼠系和细胞态，我们可以根据先前验证的元素和编码人类结果来解释结果。我们将使用编码标准来用于高吞吐量，基于序列的测定，以确定七种小鼠细胞类型中的基因表达，DNase超敏位点，组蛋白修饰和选定的转录因子占有率。八个选定的功能是功能最有用的功能，因此对于与人类数据进行比较最有用。在AIM 2中，我们应用了染色体构象捕获的全基因组实现，以在两种细胞类型中绘制转录因子结合位点及其反应性基因之间的相互作用。这些结果将与编码开发项目中的结果进行比较。 AIM 3中的比较分析将确保我们产生的数据的影响将超出单个小鼠细胞系统本身。为此，我们在多个机构中组织了调查人员的合作，其中每个小组都是一个或多个关键方面的专家。我们的数据通过编码公开且可访问，将在2年刺激中和编码之后加速和加速许多未来的研究。这响应了NHGRI要求对“通过对小鼠基因组进行平行的努力来增强人类编码项目价值的应用程序”。提出的工作将改善人类生物功能性DNA序列的图，这反过来又有助于解释人类基因组序列中的变体如何与人类疾病有关，从而导致候选有效治疗和预防的新途径。公共卫生相关性：每个人对病原体的反应都有不同，并且可能患有癌症，心脏病或糖尿病等复杂疾病。个人对疾病的敏感性部分取决于遗传学，我们可以高精度地绘制与疾病易感性相关的DNA变异的位置。为了了解这些变体如何促进疾病易感性，我们需要确定所有DNA序列的生物学功能。提出的工作将有助于我们映射这些功能性DNA序列。