Biochemical Basis of Chromatin Folding and Chromosome Condensation

染色质折叠和染色体缩合的生化基础

• 批准号: 9351824
• 负责人: Kyle Patrick Eagen
• 金额: $ 39.5万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9351824
• 关键词: Acute T Cell Leukemia; Affect; Biochemical; Biological Process; Biology; Cell Nucleus; Cells; Cellular biology; Chemicals; Chromatin; Chromatin Fiber; Chromatin Structure; Chromosome Condensation; Chromosome Structures; Chromosomes; Congenital Abnormality; Congenital Limb Deformities; DNA; DNA Folding; Data; Disease; Functional disorder; Gene Expression Regulation; Genomics; Glioma; Goals; Hair; Heredity; High-Throughput DNA Sequencing; Histones; Human; Interphase; Investigation; Knowledge; Lead; Ligation; Link; Malignant Neoplasms; Metaphase; Methods; Mitosis; Mitotic Chromosome; Molecular; Molecular Biology; Molecular Genetics; Nature; Nucleosomes; Outcome; Pathology; Pattern; Phosphorylation; Physical condensation; Polydactyly; Post-Translational Protein Processing; Process; Property; Regulation; Research; Resolution; Role; Stretching; Structure; Syndrome; Testing; Therapeutic; Width; Work; base; condensin; foot; holistic approach; human disease; innovation; insight; light microscopy; novel; novel therapeutics; programs; targeted treatment

PROJECT SUMMARY/ABSTRACT The long-term goal of the PI’s research program is to elucidate the molecular mechanisms, structure, and regulation of chromatin folding and chromosome condensation. The rationale for pursuing fundamental investigations into DNA folding within nuclei and chromosomes is that this folding goes awry in a number of human diseases, such as the congenital limb malformations brachydactyly, F-syndrome, and polydactyly, and cancers such as glioma and T-cell acute lymphoblastic leukemia. Fundamental studies, such as those proposed here, are needed to fully define the pathophysiology of these diseases and will serve as a basis for developing specific, targeted therapeutics. In pursuit of this long-term goal, the objective during this project period is to define DNA folding within topologically associating domains (TADs), recently discovered independently folded domains of chromatin. TADs are regions of chromatin more likely to interact with themselves than with their neighbors, and are up to 30-fold more condensed than a fully extended, “beads-on-a-string” chromatin fiber. Specific aims for this project period are: (1) identify intrinsic properties of the chromatin fiber that affect TAD folding, (2) elucidate the folding pattern of DNA within a TAD, and (3) elucidate how TAD structure changes as cells enter mitosis. These aims will be attained using an innovative, holistic approach that integrates methods from molecular genetics, molecular biology, cell biology, and genomics. The expected outcomes of this combined approach is that completion of the proposed work will reveal how DNA is folded within TADs, and how this folding changes as cells exit interphase and enter metaphase. These outcomes will have a positive impact on the field of chromosome biology by providing a better molecular understanding of chromatin folding and chromosome condensation. Such a molecular understanding is expected to ultimately reveal the impact of chromatin folding on gene regulation and cellular heredity. This fundamental knowledge is necessary for defining the pathophysiology of human disease and developing novel therapeutics.

项目总结/摘要 PI的研究计划的长期目标是阐明分子机制，结构， 染色质折叠和染色体浓缩的调节。追求根本利益的理由 对细胞核和染色体内DNA折叠的研究表明，这种折叠在许多 人类疾病，如先天性肢体畸形短指畸形、F综合征和多指畸形，以及 癌症如神经胶质瘤和T细胞急性淋巴细胞白血病。基础研究，如提议的研究 在这里，需要充分定义这些疾病的病理生理学，并将作为发展的基础。 特异性靶向治疗。为了实现这一长期目标，本项目期间的目标是 定义了拓扑相关结构域（TADs）内的DNA折叠，最近发现独立折叠 染色质的结构域。TADs是染色质中更可能与自身相互作用而不是与其自身相互作用的区域。 相邻的染色质纤维，并且比完全延伸的“串珠状”染色质纤维浓缩多达30倍。 本项目的具体目标是：（1）确定影响染色质纤维的内在特性 折叠，（2）阐明DNA的折叠模式内的一个DNA，（3）阐明如何DNA结构的变化， 细胞进入有丝分裂。这些目标将通过一种创新的、综合的方法来实现， 分子遗传学、分子生物学、细胞生物学和基因组学。预期的结果 结合的方法是，完成拟议的工作将揭示DNA是如何折叠在TADs内，以及如何 这种折叠随着细胞退出间期和进入中期而改变。这些成果将产生积极影响 通过提供对染色质折叠的更好的分子理解， 染色体浓缩这样的分子理解有望最终揭示 染色质折叠对基因调控和细胞遗传的影响。这些基本知识对于定义 人类疾病的病理生理学和开发新的治疗方法。