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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：
10593939
负责人：
Anders Sejr Hansen
金额：
$ 37.43万
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 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10593939
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 Modeling Molecular Mutation Oncogenes Patients Physical condensation Population Proteins Regulation Running Structure System Techniques Technology Testing Time Tumorigenicity Untranslated RNA Visualization blind cell fixing cell type experimental study genome editing imaging approach imaging modality imaging platform imaging study innovation live cell imaging nanometer overexpression promoter spatiotemporal superresolution imaging superresolution microscopy targeted treatment technological innovation timeline ultra high resolution

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.

项目总结

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Dynamics of endogenous PARP1 and PARP2 during DNA damage revealed by live-cell single-molecule imaging.

DOI：
10.1016/j.isci.2022.105779
发表时间：
2023-01-20
期刊：
ISCIENCE
影响因子：
5.8
作者：
Mahadevan, Jyothi;Jha, Asmita;Rudolph, Johannes;Bowerman, Samuel;Narducci, Domenic;Hansen, Anders S.;Luger, Karolin
通讯作者：
Luger, Karolin

Enhancer-promoter interactions and transcription are largely maintained upon acute loss of CTCF, cohesin, WAPL or YY1.

DOI：
10.1038/s41588-022-01223-8
发表时间：
2022-12
期刊：
NATURE GENETICS
影响因子：
30.8
作者：
Hsieh, Tsung-Han S.;Cattoglio, Claudia;Slobodyanyuk, Elena;Hansen, Anders S.;Darzacq, Xavier;Tjian, Robert
通讯作者：
Tjian, Robert