Folding, Misfolding, and Unfolding: How human 3D genome structure resists, adapts, or succumbs to physical stresses in health and disease
折叠、错误折叠和展开:人类 3D 基因组结构如何抵抗、适应或屈服于健康和疾病中的物理压力
基本信息
- 批准号:10004689
- 负责人:
- 金额:$ 36.73万
- 依托单位:
- 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:2019-09-01 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAffectArchitectureBiologicalBiological ProcessCell AgingCell NucleusCellsCharacteristicsChromosome StructuresChromosomesComplexDNA DamageDNA RepairDNA biosynthesisDependenceDiseaseEtiologyExposure toFutureGene Expression RegulationGeneticGenomeGenomic SegmentGoalsHealthHumanHuman ChromosomesHuman GenomeLamin Type ALeadLengthMalignant NeoplasmsMicroscopyMolecularNuclearPremature aging syndromeProgeriaProteinsRadiationRadiation induced damageRegulator GenesResearchRoentgen RaysRoleShapesStressStructureSystemTechniquesbasecancer cellcell motilitycell typechromosome conformation capturedisease diagnosisexperiencegenome analysismigrationmutantphysical propertyprogramsresponsethree dimensional structurex-ray irradiation
项目摘要
Project Summary/Abstract:
The 3D folding of human chromosomes inside the nucleus affects numerous fundamental biological processes,
including gene regulation, DNA repair and replication, and even the physical properties of the nucleus. Recent
research is beginning to define the key molecular factors that build the genome structure, but little is known
about how this structure responds to physical stresses experienced by cells and nuclei. The 3D genome
structure in healthy cells must withstand or respond to perturbations such as physical forces, nuclear shape
changes, and DNA damaging insults, like radiation. Disruptions in genome structure and nuclear architecture
can lead to diseases such as cancer or premature aging, so it is important that we determine the characteristics,
causes, and effects of 3D genome changes. Often, disease-related changes in 3D genome organization are
considered in isolation, i.e. “this change occurs in cancer,” but this perspective may miss common underlying
mechanisms that govern the 3D genome across many biological situations. My research program seeks to
develop an integrative view of the changes that chromosomes experience in response to physical disruptions
through a complementary set of projects. Our overarching goals are to understand how different levels of 3D
genome structure change in response to nuclear shape changes and DNA damaging radiation and how the
network of 3D contacts in the genome can accomplish both gene regulatory functions and contribute to
necessary physical properties of the nucleus. To this end, we will integrate microscopy, cutting edge
sequencing-based techniques such as chromosome conformation capture (Hi-C), and computational
approaches to investigate 3D genome disruptions in several systems, including: 1) cells exposed to DNA
damaging X-ray irradiation, 2) the initial states and adaptations of the 3D genome necessary for cell nuclei to
squeeze through tight spaces during confined migration, and 3) the aspects of genome structure that are
disrupted and maintained during cellular aging in a lamin-mutant progeria cell. Our research program has
yielded preliminary evidence that motivates further study of these systems: we have determined that the cell
actively protects its 3D genome structure after X-ray damage and that the 3D genome folding state influences
whether cancer cell nuclei can squeeze through tight spaces during metastatic migration. These results show
that a comprehensive understanding of genome structure changes is necessary to better understand disease
initiation and progression. Analyzing genome structure changes across systems will provide a unique,
integrated view of what types of genomic regions or structures are the most robust or fragile and the degree of
dependence between genome structures at different length scales. All these results will help us build a
framework in which we can understand, and eventually predict, the impact of certain treatments or conditions
on human cell types, depending on their initial genome folding state. This framework will open avenues for
future chromosome structure-based disease diagnosis and treatment.
项目概要/摘要:
人类染色体在细胞核内的3D折叠影响了许多基本的生物学过程,
包括基因调控、DNA修复和复制,甚至细胞核的物理性质。最近
研究开始确定构建基因组结构的关键分子因子,但所知甚少
关于这个结构如何对细胞和细胞核所经历的物理压力做出反应。3D基因组
健康细胞中的结构必须承受或响应于诸如物理力、核形状
变化和DNA损伤的侮辱,如辐射。基因组结构和核结构的破坏
可能导致癌症或过早衰老等疾病,因此我们确定其特征非常重要,
3D基因组变化的原因和影响。通常,3D基因组组织中与疾病相关的变化是
孤立地考虑,即“这种变化发生在癌症中”,但这种观点可能会错过共同的基础,
在许多生物情况下控制3D基因组的机制。我的研究计划旨在
发展一个综合的观点,染色体的变化经验,以响应物理破坏
通过一系列互补的项目。我们的首要目标是了解不同层次的3D
基因组结构的变化,以响应核形状的变化和DNA损伤辐射,以及如何
基因组中的3D接触网络可以实现基因调控功能,并有助于
原子核的必要物理性质。为此,我们将整合显微镜,尖端
基于测序的技术,如染色体构象捕获(Hi-C),和计算
研究几种系统中3D基因组破坏的方法,包括:1)暴露于DNA的细胞
破坏性的X射线照射,2)细胞核所必需的3D基因组的初始状态和适应,
在有限的迁移过程中挤压通过紧密的空间,和3)基因组结构的方面,
在核纤层蛋白突变的早衰细胞中细胞老化期间被破坏和维持。我们的研究计划
初步的证据激发了对这些系统的进一步研究:我们已经确定,
在X射线损伤后积极保护其3D基因组结构,并且3D基因组折叠状态影响
癌细胞核是否能在转移迁移过程中挤压通过狭窄的空间。这些结果表明
对基因组结构变化的全面了解对于更好地了解疾病是必要的,
启动和进展。跨系统分析基因组结构变化将提供一个独特的,
什么类型的基因组区域或结构是最强大或最脆弱的,
在不同长度尺度上的基因组结构之间的依赖性。所有这些结果将帮助我们建立一个
我们可以理解并最终预测某些治疗或条件的影响的框架
对人类细胞类型的影响,取决于它们最初的基因组折叠状态。这一框架将为以下方面开辟道路:
未来基于染色体结构的疾病诊断和治疗。
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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Rachel Patton McCord其他文献
How to build a cohesive genome in 3D
如何在三维空间中构建一个有凝聚力的基因组
- DOI:
10.1038/nature24145 - 发表时间:
2017-10-04 - 期刊:
- 影响因子:48.500
- 作者:
Rachel Patton McCord - 通讯作者:
Rachel Patton McCord
Polymer model integrates imaging and sequencing to reveal how nanoscale heterochromatin domains influence gene expression
聚合物模型整合了成像和测序,以揭示纳米级异染色质结构域如何影响基因表达
- DOI:
10.1038/s41467-025-59001-z - 发表时间:
2025-04-23 - 期刊:
- 影响因子:15.700
- 作者:
Vinayak Vinayak;Ramin Basir;Rosela Golloshi;Joshua Toth;Lucas Sant’Anna;Melike Lakadamyali;Rachel Patton McCord;Vivek B. Shenoy - 通讯作者:
Vivek B. Shenoy
Chromosome compartmentalization: causes, changes, consequences, and conundrums
染色体区室化:成因、变化、影响及难题
- DOI:
10.1016/j.tcb.2024.01.009 - 发表时间:
2024-09-01 - 期刊:
- 影响因子:18.100
- 作者:
Heng Li;Christopher Playter;Priyojit Das;Rachel Patton McCord - 通讯作者:
Rachel Patton McCord
Deciphering pre-existing and induced 3D genome architecture changes involved in constricted melanoma migration
解读与受限的黑色素瘤迁移相关的预先存在的和诱导产生的三维基因组结构变化
- DOI:
10.1016/j.isci.2025.112346 - 发表时间:
2025-05-16 - 期刊:
- 影响因子:4.100
- 作者:
Christopher Playter;Rosela Golloshi;Joshua H. Garretson;Alvaro Rodriguez Gonzalez;Taiwo Habeeb Olajide;Ahmed Saad;Samuel John Benson;Rachel Patton McCord - 通讯作者:
Rachel Patton McCord
Linking Yeast Transcription Factor Structural Class and Detailed Binding Preferences with in vivo Regulatory Functions
- DOI:
10.1016/j.bpj.2008.12.218 - 发表时间:
2009-02-01 - 期刊:
- 影响因子:
- 作者:
Rachel Patton McCord;Cong Zhu;Trevor W. Siggers;Martha L. Bulyk - 通讯作者:
Martha L. Bulyk
Rachel Patton McCord的其他文献
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{{ truncateString('Rachel Patton McCord', 18)}}的其他基金
Folding, Misfolding, and Unfolding: How human 3D genome structure resists, adapts, or succumbs to physical stresses in health and disease
折叠、错误折叠和展开:人类 3D 基因组结构如何抵抗、适应或屈服于健康和疾病中的物理压力
- 批准号:
10202663 - 财政年份:2019
- 资助金额:
$ 36.73万 - 项目类别:
Folding, Misfolding, and Unfolding: How human 3D genome structure resists, adapts, or succumbs to physical stresses in health and disease
折叠、错误折叠和展开:人类 3D 基因组结构如何抵抗、适应或屈服于健康和疾病中的物理压力
- 批准号:
10437707 - 财政年份:2019
- 资助金额:
$ 36.73万 - 项目类别:
Folding, Misfolding, and Unfolding: How human 3D genome structure resists, adapts, or succumbs to physical stresses in health and disease
折叠、错误折叠和展开:人类 3D 基因组结构如何抵抗、适应或屈服于健康和疾病中的物理压力
- 批准号:
10649479 - 财政年份:2019
- 资助金额:
$ 36.73万 - 项目类别:
The Effects of Physical Disruption on Genome Organization and Integrity
物理破坏对基因组组织和完整性的影响
- 批准号:
8417791 - 财政年份:2012
- 资助金额:
$ 36.73万 - 项目类别:
The Effects of Physical Disruption on Genome Organization and Integrity
物理破坏对基因组组织和完整性的影响
- 批准号:
8256197 - 财政年份:2012
- 资助金额:
$ 36.73万 - 项目类别:
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