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: 10112283
• 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/10112283
• 关键词: 3-Dimensional; ATAC-seq; Adaptive Immune System; Affect; Agreement; Allergic; Architecture; Autoimmune; 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; Hi-C; 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进化的关键力量。结果， 基因表达进化的机制已成为人们强烈关注的主题。一些 研究人员测量了染色质、mRNA 和蛋白质基因表达的进化变化 水平，从而对物种如何进化产生新的见解。然而，基因表达不同阶段的研究 并不总是意见一致。例如，进化变化的速度极快， 在增强子中广泛观察到的结果似乎与 mRNA 丰度中观察到的较慢速率相冲突。我们 最近完成的一项针对灵长类动物的重大比较研究表明，增强子和增强子之间的这种差异 mRNA 的进化部分反映了增强子的广泛补偿，这些增强子共同决定转录 目标基因。同样，相关研究结果表明，转录后改变缓冲蛋白 mRNA 表达中相对更常见的差异。总之，这些最近的发现 证明影响转录调控多个阶段的进化变化通常具有 对基因表达的相互依赖的影响。 在这里，我们建议确定转录调控早期阶段如何协同工作 通过跨阶段的补偿性变化来保护基因表达，或者在极少数情况下改变 mRNA 以改变生物体表型的方式。我们的中心假设是阶段之间的相互作用是常见的， 尤其是在长的进化时间尺度上。为了检验这个假设，我们提出了一个雄心勃勃的计划来收集财富 基因组数据分析了九种哺乳动物的两种细胞类型和三种组织中基因表达的不同阶段 物种。我们的研究重点是 mRNA 生产中的几个早期限速步骤，利用分子生物学技术 选择提供有关染色质结构的正交信息源的测定 (Hi-C/Hi-ChIP)， 可及性 (ATAC-seq)、转录 (PRO-seq) 和 mRNA 水平 (RNA-seq)。该项目将生产 迄今为止在哺乳动物中统一收集的最大的基因组数据资源。我们将整合基因组数据 使用一套新的计算工具，这些工具一起将提供对如何区分的新理解 在监管演变过程中，监管阶段协同工作。