Super-resolution microscopy for dynamic analysis of focal enhancer amplifications in cancer

用于癌症焦点增强子扩增动态分析的超分辨率显微镜

基本信息

批准号：
10170545
负责人：
Anders Sejr Hansen
金额：
$ 38万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-05 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10170545
关键词：
3-Dimensional A549 Acute Address Adenocarcinoma Cell Affect Automobile Driving Body of uterus Cancer Etiology Carcinoma Cells Chemicals Code Communication Communities DNA Disputes Distal Elements Endometrial Carcinoma Enhancers Event Gene Activation Gene Expression Genes Genetic Diseases Genetic Enhancer Element Genetic Transcription Genome Genomics Goals Histones Human Image Individual Label Lung Adenocarcinoma MYC gene Malignant Epithelial Cell Malignant Neoplasms Maps Measures Mediating Methods Microscopy Modeling Molecular Mutation Oncogenes Patients Population Proteins Regulation Resolution Running Structure System Techniques Technology Testing Time TimeLine Tumorigenicity Untranslated RNA Visualization base blind cancer genetics cell type cellular imaging experimental study genome editing imaging approach imaging modality imaging platform imaging study innovation live cell imaging nanometer overexpression promoter spatiotemporal targeted treatment technological innovation

项目摘要

Project Summary Cancer is often thought of as a genetic disease. For example, specific protein-coding mutations can activate cancer-causing oncogenes. However, cancer-causing oncogene can also be activated by alterations to non-coding DNA. Specifically, enhancers are non-coding DNA elements that can activate gene expression across vast genomic distances. In numerous cancers, genetic alterations cause enhancers to over-activate cancer-causing oncogenes. This is also referred to as enhancer hijacking. Here we focus on epithelial cancers, where enhancers that activate the MYC oncogene get duplicated and focally amplified. This correlates with higher MYC expression and increased tumorigenicity. But the molecular mechanisms are not well understood. Achieving a mechanistic understanding is important since it may identify molecular ‘Achilles Heels’ that can be targeted therapeutically. Achieving an understanding of the mechanism of enhancer action in general and enhancer hijacking in cancer in general requires an ability to measure at high spatiotemporal precision enhancer-gene communication in living cells. The proposed project will establish and validate such a platform based on super-resolution microscopy, which make it possible to track individual enhancers and genes with a precision of ten nanometers in living cells as well as gene activity in real time. Significant efforts will be devoted to validating the super- resolution microscopy approach through extensive control experiments. Significant efforts will also be devoted to disseminating the technological innovations and know-how to the greater community. In summary, we propose to establish and validate an innovative and integrative experimental and computational super-resolution microscopy platform for studying focal enhancer amplifications. While our initial focus is on amplifications of MYC enhancers in epithelial cancers, the proposed platform is likely to find widespread use beyond MYC.

项目概要癌症通常被认为是一种遗传疾病，例如，特定的蛋白质编码突变可以导致癌症。激活致癌基因然而，致癌基因也可以通过改变来激活。具体来说，增强子是可以激活基因表达的非编码DNA元件。在许多癌症中，基因改变会导致增强子过度激活。这也称为增强子劫持。在这里，我们重点关注上皮癌，其中激活 MYC 癌基因的增强子会被复制这与较高的 MYC 表达和增加的致瘤性相关。分子机制尚未得到很好的理解，因为它可能会影响分子机制。识别可以靶向治疗的分子“致命弱点”。了解增强子作用的一般机制和增强子劫持的机制一般来说，癌症需要具有高时空精度测量增强子-基因通讯的能力拟议的项目将建立并验证这样一个基于超分辨率的平台。显微镜，可以以十纳米的精度追踪单个增强子和基因活细胞以及基因活动的实时验证将投入大量精力。通过控制实验的分辨率显微镜方法也将得到广泛的投入。向更广泛的社区传播技术创新和专业知识。总之，我们建议建立并验证一个创新和综合的实验和用于研究焦点增强子放大的计算超分辨率显微镜平台。重点是上皮癌中 MYC 增强子的扩增，所提出的平台可能会发现 MYC 之外的广泛使用。