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Principals of Chromatin Organization

染色质组织的负责人

基本信息

批准号：
10225461
负责人：
Michael Jordan Rowley
金额：
$ 24.9万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10225461
关键词：
3-Dimensional Affect Algorithms Animal Model Architecture Award Caenorhabditis elegans Cell Nucleus Cells ChIP-seq Chemicals Chromatin Chromosome Structures Chromosomes Complex Data Development Distal Dosage Compensation (Genetics)Drosophila genus Embryo Enhancers Gene Expression Genes Genetic Genetic Transcription Genome Genomics Goals Hi-C Human Individual Mammals Maps Mentorship Methods Microscopy Modeling Mutation Organism Pattern Phase Play Population Proteins Recovery Research Research Personnel Resolution Role Site Spottings Structure System Techniques Testing Training Transcription Elongation Transcriptional Activation Visualization Work X Chromosome algorithm development autosome experimental study genome-wide analysis global run on sequencing prediction algorithm preference promoter recruit segregation tool transcription factor transcriptome sequencing

项目摘要

Project Summary Gene expression is controlled by transcription factors that are often bound to chromatin hundreds of kilobases away. This long-range control of gene expression is accomplished through chromatin interactions as part of the 3D organization of the genome. Genome-wide studies of chromatin interactions (Hi-C) have identified several patterns of chromatin organization including compartments, topologically associated domains (TADs), and high intensity point-to-point loops. Fundamental principles causing the formation of these structures are not understood. For example, human cells form high intensity loops that are associated with CTCF and are dependent on its motif’s orientation. A loop extrusion model has been proposed to explain this feature of mammalian CTCF motif orientation, but the mechanistic principle behind this phenomenon is unknown. I found that in Drosophila, CTCF does not form high intensity loops and the motif orientation does not correlate with any interaction preferences. Instead, non-CTCF loops occur in early development, but disappear in later stages when compartments and TADs appear. In C. elegans, which lacks CTCF altogether, high intensity loops correspond to dosage compensation complex recruitment sites. My preliminary work in analyzing C. elegans data indicates that a network of these loops spans the X chromosome. One major goal of this project is to discover fundamental principles of loop formation. Aim1 of this project will A) exploit the differences between CTCF looping in humans and Drosophila to determine how human CTCF loops form, B) explore the relationship of loops to TADs and compartments throughout development, and C) test whether or not loops create a network of interactions that contributes to the overall X chromosome structure and gene expression control in C. elegans. My previous work has indicated that transcription plays an important role in compartment and TAD formation, a feature that can be somewhat obscured by the prominent role of architectural proteins, like CTCF. Aim2 of this project will confirm the role of transcriptional elongation in chromatin organization and will decipher the individual roles of architectural proteins and transcriptional activity in compartment and TAD formation. These findings will contribute to refining a preliminary algorithm that can simulate chromatin organization at high resolution, giving researchers the ability to predict the effects of mutations or chromatin aberrations on TAD structure. The experiments within these aims will be initiated during the K99 phase of the award and will include training on genetic methods and the considerations necessary for working with Drosophila and C. elegans. This training will provide me with the tools and mentorship necessary for a successful transition to independent research during the R00 phase.

项目摘要基因的表达是由转录因子控制的，这些转录因子通常与染色质数百个碱基结合离开。这种对基因表达的远程控制是通过染色质相互作用完成的，作为基因组的3D组织。全基因组染色质相互作用研究(Hi-C)已经确定了几个染色质组织的模式，包括隔间、拓扑相关结构域(TADS)和高强度点对点环路。导致这些结构形成的基本原理并不是明白了。例如，人类细胞形成与CTCF相关的高强度环路，并取决于其主题的方向。提出了一个环状挤出模型来解释这一特征哺乳动物的CTCF基序定向，但这种现象背后的机制原理尚不清楚。我发现在果蝇中，CTCF不形成高强度环，基序取向与任何交互首选项。相反，非CTCF循环在早期开发中出现，但在以后消失出现隔间和TADS的阶段。在完全缺乏CTCF的线虫中，高强度循环对应于剂量补偿复杂的招聘地点。我在分析C. Elgans的数据表明，X染色体上有一个由这些环组成的网络。这个项目的一个主要目标是就是发现环路形成的基本原理。这个项目的目的是A)利用这些差异为了确定人类和果蝇的CTCF环路是如何形成的，B)探索在整个开发过程中循环与TADS和隔间的关系，以及C)测试循环是否创建一个相互作用的网络，对整个X染色体结构和基因表达做出贡献线虫的控制力。我以前的工作已经表明转录在隔室中起着重要的作用和TAD形成，这一特征可能会被建筑蛋白的突出作用所掩盖，比如CTCF。该项目的AIM2将证实转录延长在染色质组织和将破译建筑蛋白和转录活性在隔室和TAD中的个体作用队形。这些发现将有助于完善可以模拟染色质的初步算法以高分辨率组织，使研究人员能够预测突变或染色质的影响 TAD结构的像差。这些目标内的实验将在K99阶段启动该奖项将包括关于遗传方法的培训和与果蝇和线虫。这次培训将为我提供必要的工具和指导，以便在R00阶段成功过渡到独立研究。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Regulation of CTCF loop formation during pancreatic cell differentiation.

DOI：
10.1038/s41467-023-41964-6
发表时间：
2023-10-09
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Lyu, Xiaowen;Rowley, M. Jordan;Kulik, Michael J.;Dalton, Stephen;Corces, Victor G.
通讯作者：
Corces, Victor G.

Implications of Dosage Deficiencies in CTCF and Cohesin on Genome Organization, Gene Expression, and Human Neurodevelopment.