Evolution of Chromatin Architecture and Transcriptional Regulation in Mammals

哺乳动物染色质结构的进化和转录调控

• 批准号: 9919607
• 负责人: Charles Grahe Danko
• 金额: $ 67.76万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9919607
• 关键词: 3-Dimensional; ATAC-seq; Adaptive Immune System; Affect; Agreement; Allergic; Architecture; Autoimmune Process; Automobile Driving; Binding; Biological Assay; Blood; Brain; Buffers; CD4 Positive T Lymphocytes; Canis familiaris; Cells; Chromatin; Comparative Study; Conflict (Psychology); Data; Deoxyribonuclease I; Disease; Enhancers; Environmental Risk Factor; Equus caballus; Etiology; Evolution; Felis catus; Financial compensation; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genetic Variation; Hamsters; Human; Individual; Infertility; Inherited; Kinetics; Liver; Macaca; Mammals; Measures; Messenger RNA; Modeling; Molecular; Molecular Conformation; Mus; Muscle; Organism; Outcome; Papio; Phenotype; Phylogeny; Post-Transcriptional Regulation; Primates; Production; Proteins; RNA Stability; Rattus; Regulation; Research; Research Personnel; Resolution; Resources; Rodent; Shapes; Source; Spermatocytes; Spermatogenesis; Statistical Methods; Testing; Time; Tissues; Transcriptional Regulation; Triage; Variant; Work; cell type; comparative; comparative genomics; computerized tools; differential expression; driving force; genomic data; human disease; insight; interest; mRNA Expression; mRNA Transcript Degradation; novel; pressure; promoter; single-cell RNA sequencing; transcriptome sequencing

PROJECT ABSTRACT Changes in gene expression are a critical force driving the evolution of form and function. As a result, the mechanisms by which gene expression evolves have become a subject of intense interest. A number of investigators have measured evolutionary changes in gene expression at the chromatin, mRNA, and protein levels, leading to new insights about how species evolve. However, studies of different stages in gene expression have not always been in agreement. For example, the extremely rapid rates of evolutionary changes that have been widely observed at enhancers appear to conflict with the slower rates observed in mRNA abundance. We recently completed a major comparative study in primates showing that this disparity between enhancer and mRNA evolution, in part, reflects extensive compensation at enhancers that jointly determine transcription at target genes. Likewise, related findings have demonstrated that post-transcriptional changes buffer protein abundance to relatively more common differences in mRNA expression. Together, these recent findings demonstrate that evolutionary changes affecting multiple stages of transcriptional regulation often have interdependent effects on gene expression. Here we propose to determine how stages early during transcriptional regulation work in concert, either to conserve gene expression through compensatory changes across stages, or, in rare cases, to change mRNA in ways that alter organism phenotypes. Our central hypothesis is that interactions between stages are common, especially at long evolutionary time-scales. To test this hypothesis we propose an ambitious plan to collect rich genomic data profiling distinct stages of gene expression in two cell types and three tissues from nine mammalian species. We have focused our study on several early rate-limiting steps in mRNA production, using molecular assays selected to provide orthogonal sources of information about chromatin architecture (Hi-C/Hi-ChIP), accessibility (ATAC-seq), transcription (PRO-seq), and mRNA levels (RNA-seq). This project will produce the largest resource of genomic data uniformly collected across mammals to date. We will integrate genomic data using a suite of new computational tools, which together will provide a new understanding of how distinct regulatory stages work in concert during regulatory evolution.

项目摘要 基因表达的变化是推动形式和功能演变的关键力。结果， 基因表达发展的机制已成为引起人们强烈关注的主题。许多 研究者测量了染色质，mRNA和蛋白质基因表达的进化变化 水平，导致有关物种如何发展的新见解。但是，基因表达不同阶段的研究 并不总是同意。例如，具有极快的进化变化速率 在增强剂上广泛观察到与在mRNA丰度中观察到的速度较慢相抵触。我们 最近在灵长类动物中完成了一项主要的比较研究，表明增强剂和 mRNA进化部分反映了增强子的广泛补偿，这些补偿是共同确定在 靶基因。同样，相关的发现证明了转录后变化缓冲蛋白 在mRNA表达中相对常见的差异的丰富性。这些最近的发现在一起 证明影响转录调节多个阶段的进化变化通常具有 相互依赖的对基因表达的影响。 在这里，我们建议确定转录监管工作期间的早期阶段，要么 通过跨阶段的补偿性变化或在极少数情况下改变mRNA来保护基因表达 以改变生物表型的方式。我们的核心假设是，阶段之间的相互作用很普遍， 特别是在长期进化时尺度上。为了检验这一假设，我们提出了一个雄心勃勃的计划来收集富人 基因组数据谱图在两种细胞类型中的基因表达的不同阶段和九个哺乳动物的三个组织 物种。我们使用分子将研究重点放在mRNA产生的几个早期速率限制步骤上 选择用于提供有关染色质体系结构（HI-C/HI-CHIP）的正交源的测定源， 可访问性（ATAC-SEQ），转录（Pro-Seq）和mRNA水平（RNA-Seq）。这个项目将产生 迄今为止，基因组数据的最大资源统一收集。我们将整合基因组数据 使用一套新的计算工具，这些工具将共同提供新的了解 监管阶段在监管进化过程​​中协同工作。