Regulation of chromatin folding in space and time

染色质折叠在空间和时间上的调节

• 批准号: 10622801
• 负责人: Eric F. Joyce
• 金额: $ 48.75万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10622801
• 关键词: Aneuploidy; Architecture; Biological Assay; Cell Nucleus; Cells; Chromatin; Chromatin Loop; Chromosome Positioning; Chromosomes; Complex; DNA; Development; Disease; Enhancers; Fluorescent in Situ Hybridization; Genes; Genetic Transcription; Genome; Genomics; Goals; In Situ; Inherited; Malignant Neoplasms; Methods; Mitotic Recombination; Molecular; Nuclear; Positioning Attribute; Prevention; Proteins; Public Health; Regulation; Resolution; Technology; Time; Work; candidate identification; gene function; genetic information; new therapeutic target; novel; three dimensional structure; tool

Abstract Eukaryotic genomes encode genetic information in their linear sequence, but appropriate expression of their genes requires chromosomes to fold into complex and spatially distinct three-dimensional structures. Recent advances in genomic-based approaches have uncovered a hierarchy of DNA interactions, from small chromatin loops that connect genes and enhancers to larger chromosomal domains and nuclear compartments. However, despite the remarkable conservation of these organizational features and their impact on gene function, we have a very limited understanding of how chromosomes are spatially partitioned, functionally packaged, and relatively positioned in the nucleus. Technical limitations have also hindered our ability to ask questions regarding cell-to-cell variability and the relationship between chromatin folding, positioning, and function at single cell resolution. Our previous studies involved the development of two technologies that use fluorescent in situ hybridization (FISH) to interrogate chromosome positioning at single-cell resolution. Our goal is to build on this work and use these tools to elucidate how chromosomal segments find each other and then form stable interactions within cells. To this end, we have developed a rapid and precise method for identifying candidates involved in chromosome interactions. We now propose to employ this technology to isolate novel architectural proteins, which will be followed by a battery of genomic and in situ-based assays to characterize the candidates. Collectively, the studies proposed here will uncover novel molecular mechanisms underlying nuclear organization, providing a new avenue to study how chromatin folding and positioning is established and inherited, and how dysfunctional organization contributes to disease.

摘要 真核生物基因组以线性序列编码遗传信息，但适当表达 它们的基因需要染色体折叠成复杂且空间上不同的三维结构。 基于基因组学方法的最新进展揭示了DNA相互作用的层次结构，从小到大， 染色质环，将基因和增强子连接到更大的染色体结构域和核 隔间然而，尽管这些组织特征及其 基因功能的影响，我们对染色体如何在空间上划分的理解非常有限， 功能性包装，并相对定位在核中。技术限制也阻碍了我们的 能够提出关于细胞间变异性和染色质折叠之间关系的问题， 定位，并在单细胞分辨率下发挥作用。 我们以前的研究涉及两种技术的发展，使用荧光原位 杂交（FISH）以单细胞分辨率询问染色体定位。我们的目标是在此基础上 工作和使用这些工具来阐明染色体片段如何找到对方，然后形成稳定的 细胞内的相互作用。为此，我们开发了一种快速而精确的方法来识别候选人 参与染色体的相互作用。我们现在建议使用这项技术来分离新的建筑 蛋白质，随后将进行一系列基因组和原位分析，以表征 候选人总的来说，这里提出的研究将揭示新的分子机制， 核组织，提供了一个新的途径来研究如何染色质折叠和定位的建立 和遗传，以及功能失调的组织如何导致疾病。

项目成果

Multi-feature clustering of CTCF binding creates robustness for loop extrusion blocking and Topologically Associating Domain boundaries.

• DOI: 10.1038/s41467-023-41265-y
• 发表时间: 2023-09-12
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Chang LH;Ghosh S;Papale A;Luppino JM;Miranda M;Piras V;Degrouard J;Edouard J;Poncelet M;Lecouvreur N;Bloyer S;Leforestier A;Joyce EF;Holcman D;Noordermeer D
• 通讯作者: Noordermeer D

Condensin II drives large-scale folding and spatial partitioning of interphase chromosomes in Drosophila nuclei.

• DOI: 10.1371/journal.pgen.1007393
• 发表时间: 2018-07
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Rosin LF;Nguyen SC;Joyce EF
• 通讯作者: Joyce EF

Co-depletion of NIPBL and WAPL balance cohesin activity to correct gene misexpression.

• DOI: 10.1371/journal.pgen.1010528
• 发表时间: 2022-11
• 期刊: PLoS genetics
• 影响因子: 4.5

Programmable Chromosome Painting with Oligopaints.

使用 Oligopaints 进行可编程染色体绘画。

• DOI: 10.1007/978-1-4939-9674-2_11
• 发表时间: 2019
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Nguyen,SonC;Joyce,EricF
• 通讯作者: Joyce,EricF