Evolution of Chromatin Architecture and Transcriptional Regulation in Mammals

项目摘要 基因表达的变化是驱动形式和功能进化的关键力量。结果导致 基因表达进化的机制已成为人们强烈关注的课题。一些 研究人员已经测量了染色质、mRNA和蛋白质基因表达的进化变化， 水平，导致对物种如何进化的新见解。然而，对基因表达不同阶段的研究 并不总是一致的。例如，进化变化的极快速度， 在增强子中广泛观察到的这种速率似乎与在mRNA丰度中观察到的较慢速率相冲突。我们 最近完成了一项主要的灵长类动物比较研究，显示增强子和 mRNA的进化，部分地反映了增强子的广泛补偿，增强子共同决定转录， 目标基因。同样，相关研究结果表明，转录后变化缓冲蛋白 丰度到mRNA表达中相对更常见的差异。总之，这些最新的发现 这表明，影响转录调控多个阶段的进化变化往往具有 对基因表达的相互影响。 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存基因表达，或者在极少数情况下，改变mRNA 改变生物体的表型。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， 基因组数据描绘了来自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 物种我们的研究集中在mRNA产生的几个早期限速步骤上，使用分子生物学方法， 选择用于提供关于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）。该项目将产生 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，这些工具将共同提供一个新的理解， 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.