The RNA structural code underlying pathological regulation of RNA splicing in metastasis

转移中RNA剪接病理调控的RNA结构密码

基本信息

批准号：
10358636
负责人：
Hani Goodarzi
金额：
$ 35.31万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10358636
关键词：
Address Alternative Splicing Awareness Binding Binding Sites Biochemical Bioinformatics Biological Assay Biology Breast Cancer Patient Breast cancer metastasis Clinical Code Collaborations Communities Complex Comprehensive Cancer Center Computational Biology Dissection Elements Enhancers Event Exons Family Genetic Transcription Genomics Goals Human In Vitro Knowledge Malignant Neoplasms Measurement Mediating Messenger RNA Metastatic breast cancer Methodology Modeling Molecular Mus Mutation Neoplasm Metastasis Nonmetastatic Pathologic Pathway interactions Patients Play Positioning Attribute Post-Transcriptional Regulation Protein Isoforms Public Health RNA RNA Processing RNA Sequences RNA Splicing RNA-Binding Proteins Regulation Regulatory Element Regulatory Pathway Regulon Reporter Research Role Sampling Small Nuclear Ribonucleoproteins Structure Survival Analysis Trans-Splicing Transcript Up-Regulation Work Xenograft procedure base breast cancer progression cancer cell clinically relevant computer framework experimental study in silico in vivo innovation interdisciplinary approach knock-down lung colonization mouse model novel overexpression patient derived xenograft model programs promoter shape analysis targeted treatment tumor progression tumorigenesis

项目摘要

PROJECT SUMMARY Widespread aberrant splicing is now considered a hallmark of cancer, and many of the resulting transcript isoforms have been functionally implicated in tumorigenesis. However, the underlying regulatory pathways that govern RNA splicing and the extent to which they play a role in cancer progression remain largely unknown. Due to our limited knowledge of splicing regulation, we cannot solely rely on annotated pathways to study changes in transcript isoforms. Moreover, bioinformatic strategies that are often used in discovering transcriptional regulatory pathways often fail to capture the complexities of post-transcriptional regulation. For example, common methodologies for cis-element discovery focus on sequence alone and largely ignore the integral role of the RNA structural code in splicing. To address this challenge, we have developed a computational framework that performs context-aware analysis of alternative splicing events to identify known and novel regulators of RNA processing. Using this approach, we have discovered and partly characterized a previously unknown RNA structural splicing enhancer (SSE) that drives aberrant splicing in highly metastatic breast cancer. We have identified the associated RNA-binding protein that serves as the trans factor that interacts with this novel SSE. We have shown that this pathway drives metastatic progression in xenograft mouse models and that its activity is strongly associated with poor survival in patients. In this proposal, we will build on this previous work to (i) perform a detailed dissection of this non-canonical regulatory pathway of alternative splicing, its underlying molecular machinery, and its governing RNA structural code; (ii) evaluate the contribution of this pathway to breast cancer progression; and (iii) establish the clinical relevance of this pathway and its regulon to cancer.

项目摘要现在，广泛的异常剪接被认为是癌症的标志，许多由此产生的成绩单同工型在功能上与肿瘤发生有关。但是，基本的监管途径控制RNA剪接以及它们在癌症进展中发挥作用的程度仍然很大未知。由于我们对剪接法规的了解有限，我们不能仅依靠注释的途径来学习转录本同工型的变化。而且，经常用于发现的生物信息学策略转录调节途径通常无法捕获转录后调节的复杂性。为了例如，顺式元素发现的常见方法专注于单独的序列，并在很大程度上忽略了 RNA结构代码在剪接中的积分作用。为了应对这一挑战，我们已经开发了对替代剪接事件进行上下文感知分析的计算框架以识别已知的和RNA处理的新型调节剂。使用这种方法，我们发现并部分表征了以前未知的RNA结构剪接增强子（SSE）在高度转移中驱动异常剪接乳腺癌。我们已经确定了相关的RNA结合蛋白，该蛋白是反式因子与这部小说SSE互动。我们已经表明，该途径驱动异种移植中的转移性进展小鼠模型，其活性与患者的存活不良密切相关。在此提案中，我们将基于以前的工作（i）对这种非规范的监管途径进行详细的解剖替代剪接，其潜在的分子机械及其管理RNA结构代码；（ii）评估这种途径对乳腺癌进展的贡献；（iii）建立了这一点的临床相关性途径及其对癌症的调节。