Evolution of Chromatin Architecture and Transcriptional Regulation in Mammals

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。因此， 基因表达进化的机制已经成为人们非常感兴趣的话题。一批 研究人员测量了染色质、信使核糖核酸和蛋白质基因表达的进化变化。 水平，从而对物种如何进化有了新的见解。然而，对基因表达不同阶段的研究 并不总是意见一致。例如，进化变化的极快速度 在增强剂中被广泛观察到，似乎与在信使核糖核酸丰度中观察到的较慢的速率相冲突。我们 最近完成了一项对灵长类动物的重大比较研究，表明增强剂和增强剂之间的这种差异 在一定程度上，mrna的进化反映了共同决定转录的增强子的广泛补偿。 靶基因。同样，相关发现表明，转录后的变化缓冲蛋白 丰度相对较常见的差异在于mRNA表达的差异。总而言之，这些最新的发现 证明影响转录调控的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的早期阶段如何协同工作，或者 通过跨阶段的补偿性改变来保存基因表达，或者在极少数情况下，改变mRNAs 以改变有机体表型的方式。我们的中心假设是，阶段之间的相互作用是常见的， 特别是在很长的进化时间尺度上。为了验证这一假设，我们提出了一个雄心勃勃的计划来收集富人 九种哺乳动物两种细胞类型和三种组织中不同阶段基因表达的基因组数据 物种。我们的研究集中在信使核糖核酸产生的几个早期限速步骤上，使用分子 选择用于提供关于染色质结构(Hi-C/Hi-ChIP)的正交源的分析， 可及性(atac-seq)、转录(Proseq)和信使核糖核酸(RNA-seq)水平。这个项目将产生 迄今为止在哺乳动物中统一收集的最大基因组数据来源。我们将整合基因组数据 使用一套新的计算工具，这些工具共同提供了对如何区分 在监管演变过程中，监管阶段协同工作。

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.