Project 3: UW-CNOF Biological Validation Development
项目 3:UW-CNOF 生物验证开发
基本信息
- 批准号:9021414
- 负责人:
- 金额:$ 49.94万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-09-30 至 2020-07-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAllelesArchitectureBiologicalBiological AssayBiological ModelsCell CycleCell LineCell NucleusCell physiologyCellsChromatinChromosomesClone CellsClustered Regularly Interspaced Short Palindromic RepeatsComplementComputing MethodologiesDNADataData AnalysesDeoxyribonucleasesDetectionDevelopmentDiploid CellsEffectivenessEmbryoEngineeringEnhancersEpigenetic ProcessFemaleGene ExpressionGenerationsGenesGenetic PolymorphismGenomeGenomic SegmentGuide RNAHaploidyHumanIn VitroK-562KnowledgeLinkMammalsMapsMeasuresMediatingMediator of activation proteinMethodsModelingMolecular ConformationMusMyoblastsNuclearNuclear StructurePopulationProcessPromoter RegionsProtocols documentationPublishingRNARegulationResolutionSiteSkeletal MyoblastsStagingStructureSystemTestingTissuesTranscriptional RegulationUniversitiesValidationWashingtonWorkX ChromosomeX Inactivationabstractingautosomebasebiological systemscell typecohesincombinatorialdata modelingdesignembryonic stem cellgenome editingimprintin vivointernal controlmodel developmentnovel strategiespromoterstemstem cell differentiationtechnology developmentthree dimensional structure
项目摘要
ABSTRACT – PROJECT 3: UW-CNOF BIOLOGICAL VALIDATION DEVELOPMENT
The complexity of hierarchical interactions within the nucleus demands that easy-to-use and accurate methods
for mapping and modeling both close-range and long-range interactions be developed. In this project, the
experimental and computational methods developed in Projects 1 and 2 will be put to the test to evaluate their
ability to detect interactions at high resolution, as well as for the prediction of the sequence determinants of
specific aspects of genome architecture. In Aim 1, we will apply newly developed methods to well-defined
mouse and human biological systems in which the 4D structure of specific genomic regions and chromosomes
can be anticipated. Our validation strategy will employ systems in which alleles can be identified to facilitate
studies of diploid cells, i.e. tissues and cell lines from a mouse interspecific cross. Interactions between loci will
be tested at enhancer/promoter regions, while interactions at topologically associated domains (TADs) will be
tested by comparing the active and inactive X chromosomes in female cells. This functional validation
approach will be complemented by high resolution DNA-FISH analyses to verify specific interactions. In Aim 2,
to validate our approaches for generating a 4D view of dynamic changes in nuclear structure, we will measure
interactions in single cells during the cell cycle and during mouse myoblast and embryonic stem (ES) cell
differentiation. By focusing on relatively well understood aspects of these systems, we will achieve validation
by linking dynamic changes in the nucleome to other layers of regulation. Analysis of mouse ESC
differentiation will exploit the wealth of knowledge that surrounds X inactivation, a process central to nuclear
remodeling in mammals, while skeletal myoblast differentiation is well characterized with respect to its
transcriptional regulation. In Aim 3, we will validate our ability to predict the sequence determinants of genome
architecture. Specifically, we will perform controlled manipulations of defined genomic regions, either by allele-
specific heterozygous CRISPR/Cas9 targeting to generate cells with engineered deletions at
promoter/enhancer interacting regions and at regions between TADs, or by Xist-mediated silencing of full
autosomes. The biological validation work performed in all aims of this project will facilitate the progressive
optimization of both bulk and single cell DNase Hi-C protocols (Project 1) and new approaches to modeling the
4D nucleome (Project 2), while also paving the way for biological model development and data generation
(Project 4).
摘要 – 项目 3:UW-CNOF 生物验证开发
细胞核内层次相互作用的复杂性要求易于使用且准确的方法
为了绘制和建模,需要开发近距离和远程交互。在这个项目中,
项目 1 和 2 中开发的实验和计算方法将进行测试,以评估其效果
能够以高分辨率检测相互作用,以及预测序列决定因素
基因组结构的具体方面。在目标 1 中,我们将应用新开发的方法来明确定义
小鼠和人类生物系统,其中特定基因组区域和染色体的 4D 结构
可以预见。我们的验证策略将采用可以识别等位基因的系统,以促进
二倍体细胞的研究,即来自小鼠种间杂交的组织和细胞系。位点之间的相互作用将
在增强子/启动子区域进行测试,而拓扑相关域(TAD)的相互作用将
通过比较女性细胞中活跃和不活跃的 X 染色体进行测试。本次功能验证
该方法将得到高分辨率 DNA-FISH 分析的补充,以验证特定的相互作用。在目标 2 中,
为了验证我们生成核结构动态变化 4D 视图的方法,我们将测量
细胞周期期间以及小鼠成肌细胞和胚胎干 (ES) 细胞期间单细胞的相互作用
差异化。通过关注这些系统相对容易理解的方面,我们将实现验证
通过将核组的动态变化与其他调控层联系起来。小鼠ESC分析
分化将利用围绕X失活的丰富知识,X失活是核的核心过程
哺乳动物的重塑,而骨骼肌成肌细胞分化的特征在于其
转录调控。在目标 3 中,我们将验证我们预测基因组序列决定因素的能力
建筑学。具体来说,我们将通过等位基因对定义的基因组区域进行受控操作
特异性杂合 CRISPR/Cas9 靶向生成具有工程缺失的细胞
启动子/增强子相互作用区域和 TAD 之间的区域,或通过 Xist 介导的完全沉默
常染色体。在该项目的所有目标中进行的生物验证工作将促进进步
批量和单细胞 DNase Hi-C 方案的优化(项目 1)以及建模的新方法
4D 核组(项目 2),同时也为生物模型开发和数据生成铺平道路
(项目 4)。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Christine M. Disteche其他文献
Spatial and temporal organization of the genome: Current state and future aims of the 4D nucleome project
基因组的时空组织:4D 核组学项目的现状和未来目标
- DOI:
10.1016/j.molcel.2023.06.018 - 发表时间:
2023-08-03 - 期刊:
- 影响因子:16.600
- 作者:
Job Dekker;Frank Alber;Sarah Aufmkolk;Brian J. Beliveau;Benoit G. Bruneau;Andrew S. Belmont;Lacramioara Bintu;Alistair Boettiger;Riccardo Calandrelli;Christine M. Disteche;David M. Gilbert;Thomas Gregor;Anders S. Hansen;Bo Huang;Danwei Huangfu;Reza Kalhor;Christina S. Leslie;Wenbo Li;Yun Li;Jian Ma;Sheng Zhong - 通讯作者:
Sheng Zhong
Correction and Clarification: Unusual Molecular Characteristics of a Repeat Sequence Island within a Giemsa-Positive Band on the Mouse X Chromosome
修正和澄清:小鼠 X 染色体吉姆萨阳性条带内重复序列岛的异常分子特征
- DOI:
10.1073/pnas.87.23.9508a - 发表时间:
1990 - 期刊:
- 影响因子:11.1
- 作者:
Jamal Nasir;E. Fisher;Neil Brockdorff;Christine M. Disteche;Mary F. Lyon;S. D. Brown - 通讯作者:
S. D. Brown
The Gene for B7, a Costimulatory Signal for T-Cell Activation, Maps to Chromosomal Region 3ql3.3-3q21
- DOI:
10.1182/blood.v79.2.489.489 - 发表时间:
1992-01-15 - 期刊:
- 影响因子:
- 作者:
Gordon J. Freeman;Christine M. Disteche;John G. Gribben;David A. Adler;Arnold S. Freedman;James Dougery;Lee M. Nadler - 通讯作者:
Lee M. Nadler
Sceptic: pseudotime analysis for time-series single-cell sequencing and imaging data
- DOI:
10.1186/s13059-025-03679-3 - 发表时间:
2025-07-17 - 期刊:
- 影响因子:9.400
- 作者:
Gang Li;Hyeon-Jin Kim;Sriram Pendyala;Ran Zhang;Jean-Philippe Vert;Christine M. Disteche;Xinxian Deng;Douglas M. Fowler;William Stafford Noble - 通讯作者:
William Stafford Noble
KDM6A facilitates Xist upregulation at the onset of X inactivation
KDM6A 促进 X 失活开始时 Xist 的上调
- DOI:
10.1186/s13293-024-00683-3 - 发表时间:
2025-01-03 - 期刊:
- 影响因子:5.100
- 作者:
Josephine Lin;Jinli Zhang;Li Ma;He Fang;Rui Ma;Camille Groneck;Galina N. Filippova;Xinxian Deng;Chizuru Kinoshita;Jessica E. Young;Wenxiu Ma;Christine M. Disteche;Joel B. Berletch - 通讯作者:
Joel B. Berletch
Christine M. Disteche的其他文献
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{{ truncateString('Christine M. Disteche', 18)}}的其他基金
Dissecting the role of sex-linked genes and APOE e4 risk in AD
剖析 AD 中性相关基因和 APOE e4 风险的作用
- 批准号:
10299469 - 财政年份:2021
- 资助金额:
$ 49.94万 - 项目类别:
Dissecting the role of sex-linked genes and APOE e4 risk in AD
剖析 AD 中性相关基因和 APOE e4 风险的作用
- 批准号:
10677855 - 财政年份:2021
- 资助金额:
$ 49.94万 - 项目类别:
UW 4-Dimensional Genomic Organization of Mammalian Embryogenesis Center
威斯康星大学哺乳动物胚胎发生中心 4 维基因组组织
- 批准号:
10441525 - 财政年份:2020
- 资助金额:
$ 49.94万 - 项目类别:
UW 4-Dimensional Genomic Organization of Mammalian Embryogenesis Center
威斯康星大学哺乳动物胚胎发生中心 4 维基因组组织
- 批准号:
10885341 - 财政年份:2020
- 资助金额:
$ 49.94万 - 项目类别:
UW 4-Dimensional Genomic Organization of Mammalian Embryogenesis Center
威斯康星大学哺乳动物胚胎发生中心 4 维基因组组织
- 批准号:
10669573 - 财政年份:2020
- 资助金额:
$ 49.94万 - 项目类别:
UW 4-Dimensional Genomic Organization of Mammalian Embryogenesis Center
威斯康星大学哺乳动物胚胎发生中心 4 维基因组组织
- 批准号:
10265565 - 财政年份:2020
- 资助金额:
$ 49.94万 - 项目类别:
X chromosome regulation and role in aneuploidy
X 染色体调控及其在非整倍性中的作用
- 批准号:
10614939 - 财政年份:2019
- 资助金额:
$ 49.94万 - 项目类别:
X chromosome regulation and role in aneuploidy
X 染色体调控及其在非整倍性中的作用
- 批准号:
9908109 - 财政年份:2019
- 资助金额:
$ 49.94万 - 项目类别:
X chromosome regulation and role in aneuploidy
X 染色体调控及其在非整倍性中的作用
- 批准号:
10395506 - 财政年份:2019
- 资助金额:
$ 49.94万 - 项目类别:
DOSAGE COMPENSATION OF THE ACTIVE X CHROMOSOME IN MAMMALS
哺乳动物中活性 X 染色体的剂量补偿
- 批准号:
7809618 - 财政年份:2007
- 资助金额:
$ 49.94万 - 项目类别:
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