Uncovering how transcription and chromatin 3D structure impact one another during cellular activation

揭示转录和染色质 3D 结构在细胞激活过程中如何相互影响

基本信息

批准号：
10452658
负责人：
Christopher W Benner
金额：
$ 33.18万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-16 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10452658
关键词：
3-Dimensional Acute Address Affect Architecture Area Biomedical Research Cell Nucleus Cells Chromatin Chromatin Loop Communication Consensus DNA DNA Packaging Data Disease Dissociation Distal Enhancers Etiology Gene Activation Gene Expression Gene Expression Profile Genes Genetic Enhancer Element Genetic Models Genetic Transcription Genome Heat-Shock Response Hi-C Infection Interferons Learning Ligands Liquid substance Location Measurement Measures Mediating Minor Nucleic Acid Regulatory Sequences Phase Play Poly I-C Process Processed Genes RNA Polymerase II Reagent Regulation Regulatory Element Reporting Role Signal Transduction TLR3 gene Techniques Testing Transcription Elongation Transcription Initiation Transcriptional Activation Transcriptional Regulation base cell type cohesin experimental study gene induction genetic variant genome-wide improved inducible gene expression influenzavirus inhibitor programs promoter recruit response temporal measurement three dimensional structure

项目摘要

Project Summary/Abstract: The 3D packaging of chromatin within the nucleus is thought to play an important role in regulating gene expression. It is often assumed that promoters, enhancers, and other critical regulatory elements exert influence by forming loops in DNA that bring key regulatory elements into close spatial proximity. However, recent studies have shown that DNA loops have a relatively minor impact on gene expression, challenging the generality of this paradigm. In fact, most experiments that investigate the relationship between gene expression and genome 3D structure rely on correlated measurements and usually lack direct evidence that spatial DNA interactions have an impact on gene expression. In contrast, we recently discovered that transcription elongation can directly impact genome 3D structure by displacing the ring-like molecule cohesin from chromatin, leading to the loss of DNA loops. These findings and other reports suggest that we lack an adequate understanding of how chromatin looping is involved in the execution of gene expression programs. A more detailed view of how genome 3D structure and transcription regulate one another is essential to interpret how regulatory programs are encoded in the genome, and has important consequences for studying genome function in nearly all areas of biomedical research. This proposal leverages recently developed reagents and sensitive profiling techniques to investigate how genome 3D structure impacts transcription and, reciprocally, how transcription impacts genome 3D structure in response to acute cellular stimulation. Using nascent initiation profiling (Start-seq), we will systematically characterize how loss of chromatin looping impacts inducible transcription at both promoter and enhancer elements and examine how perturbation of 3D structure impacts the functional communication between distal regulatory elements and their target genes. This proposal will also explore how transcriptional activation itself may regulate chromatin loop formation or dissociation as a direct consequence of changes in transcription. These studies will help reveal how chromatin 3D structure and transcription influence each other and will help improve the interpretation of regulatory programs encoded in the genome.

项目摘要/摘要：细胞核内染色质的 3D 包装被认为在基因调控中发挥着重要作用表达。通常认为启动子、增强子和其他关键调控元件发挥作用通过在 DNA 中形成环，使关键调控元件在空间上紧密相连来产生影响。然而，最近的研究表明，DNA 环对基因表达的影响相对较小，挑战了这个范式的普遍性。事实上，大多数研究基因之间关系的实验表达和基因组 3D 结构依赖于相关测量，通常缺乏直接证据表明空间 DNA 相互作用对基因表达产生影响。相比之下，我们最近发现转录延伸可以通过取代环状分子粘连蛋白来直接影响基因组 3D 结构染色质，导致 DNA 环丢失。这些发现和其他报告表明我们缺乏充分了解染色质循环如何参与基因表达程序的执行。一个更详细地了解基因组 3D 结构和转录如何相互调节对于解释至关重要调控程序如何在基因组中编码，并对基因组研究产生重要影响几乎在生物医学研究的所有领域发挥作用。该提案利用了最近开发的试剂和敏感的分析技术来研究基因组 3D 结构如何影响转录，并且反过来，转录如何影响基因组 3D 结构以响应急性细胞刺激。使用新生起始分析 (Start-seq)，我们将系统地描述染色质环丢失如何影响启动子和增强子元件的诱导转录并检查 3D 结构的扰动影响远端调控元件与其靶基因之间的功能通讯。这个提议还将探索转录激活本身如何调节染色质环的形成或解离转录变化的直接结果。这些研究将有助于揭示染色质 3D 结构和转录相互影响，将有助于改善对编码的调控程序的解释基因组。