Core2: Transcriptomics and Chromatin Structure

核心2：转录组学和染色质结构

• 批准号: 10271570
• 负责人: Franziska Michor
• 金额: $ 35.88万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-17 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10271570
• 关键词: 3-Dimensional; Address; Affect; Biological Models; Blood Circulation; Blood Vessels; Blood capillaries; Cell Nucleus; Cell Survival; Cells; Chromatin; Chromatin Structure; Collaborations; Computer Models; DNA; Data; Disease; Event; Exposure to; Extravasation; Fostering; Future; Gene Expression; Genes; Genetic Transcription; Genome Mappings; Genomics; HDAC3 gene; Hi-C; Image; Imaging technology; In Vitro; Infrastructure; Label; Lead; Link; Mechanical Stress; Mechanics; Microscopic; Microscopy; Modeling; Molecular; Molecular Conformation; Nanoscopy; Neoplasm Metastasis; Nuclear; Optics; Organ; Pattern; Phenotype; Process; Property; Resolution; Role; Scanning; Services; Signal Pathway; Stress; Technology; Transcription Alteration; Transcription Process; Transmission Electron Microscopy; Tumor Cell Migration; Validation; cellular imaging; electron tomography; in vitro Model; in vivo; in vivo Model; interest; mRNA sequencing; mechanical properties; migration; nanoimaging; nanoscale; nanosensors; neoplastic cell; operation; optical nanoscopy; predictive modeling; programs; shear stress; single cell mRNA sequencing; single molecule; stressor; therapeutic target; transcriptional reprogramming; transcriptomics; transmission process; whole genome

Genomic and Chromatin Analysis Core (Core B): SUMMARY The Genomic and Chromatin Analysis Core (Core B) will provide services to Projects 1 and 2, in collaboration with Core A, focusing on the role of alterations in transcriptional patterns induced by intravascular stress and extravasation on extravascular survival, dormancy, and outgrowth. GCC will be responsible for analyzing transcriptional and chromatin events that are affected by and may affect tumor cell vascular and transmigration processes isolated in Projects 1 and 2. GCC will deploy state-of-the-art technologies, including single-cell mRNA sequencing, genome mapping (e.g., Hi-C), and the nanoscale imaging of chromatin structural and molecular states, and these results will be used for computational modeling of the mechanical properties and the signaling pathways involved in mechano-adaptation and chromatin perturbation (Core A). In the bloodstream and during extravasation, tumor cells are exposed to a variety of physical stressors, including mechanical damage due to shear stress and passage through narrow capillaries with substantial nuclear deformations. It is not fully understood how mechanical stress and the resulting chromatin derangement and transcriptional alterations affect the ability of tumor cells to form metastases, lead to aggressive disease, develop dormancy, and foster their overall survival ability. Core B will provide genomic and chromatin analyses that will enable the Projects to begin addressing these long-standing questions on the consequences of mechano-adaptation in metastasis. Core B will leverage single- cell mRNA sequencing for transcription analysis as well as genome mapping (Hi-C, whenever possible, or Low- input Hi-C) and a unique suite of nanoscale imaging technologies (3-D chromatin scanning transmission electron tomography, optical single-molecule nanoscopy, and optical spectroscopic nanosensing) for chromatin conformation analysis on cells generated by the model systems in the Projects. Furthermore, the data on chromatin structure, including genome mapping and chromatin conformation imaging, will be provided to Core A to enable the modeling of the mechanical and phenotypic properties of metastasizing tumor cells. Beyond the scope of the U54 Center and upon completion of the Projects, the normalization of transcriptional reprogramming might be explored for therapeutic targeting of metastasis.

基因组和染色质分析核心（核心B）：总结 基因组和染色质分析核心（核心B）将为项目1和2提供服务， 与核心A，重点是血管内应激诱导的转录模式改变的作用， 外渗对血管外存活、休眠和生长的影响。GCC将负责分析 转录和染色质事件受肿瘤细胞血管和迁移的影响，并可能影响肿瘤细胞血管和迁移 项目1和项目2中分离的过程。GCC将部署最先进的技术，包括单细胞mRNA 测序，基因组作图（例如，Hi-C）以及染色质结构和分子的纳米级成像 这些结果将用于机械性能和信号的计算建模 参与机械适应和染色质扰动的途径（核心A）。 在血流中和外渗期间，肿瘤细胞暴露于各种物理应激源， 包括由于剪切应力引起的机械损伤和通过狭窄的毛细管， 核变形目前还不完全清楚机械应力和由此产生的染色质紊乱 并且转录改变影响肿瘤细胞形成转移的能力，导致侵袭性疾病， 培养休眠能力，培养整体生存能力。 核心B将提供基因组和染色质分析，使项目能够开始解决这些问题 关于转移中机械适应的后果的长期问题。核心B将利用单一- 用于转录分析的细胞mRNA测序以及基因组作图（Hi-C，尽可能地，或Low-C）。 输入Hi-C）和一套独特的纳米级成像技术（3-D染色质扫描透射电子 断层摄影术、光学单分子纳米显微镜和光学光谱纳米传感）用于染色质 项目中模型系统生成的细胞构象分析。此外，关于 染色质结构，包括基因组图谱和染色质构象成像，将提供给核心 A，使转移肿瘤细胞的机械和表型特性的建模。超出 U 54中心的范围和项目完成后，转录重编程的正常化 可能会被探索用于转移的治疗靶向。