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

• 批准号: 10654522
• 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
• 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/10654522
• 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; 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; 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

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.

项目总结

项目成果

RPL22 is a tumor suppressor in MSI-high cancers and a key splicing regulator of MDM4.

RPL22 是 MSI 高癌症中的肿瘤抑制因子，也是 MDM4 的关键剪接调节因子。

• DOI: 10.1101/2023.12.10.570873
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Weinstein,HannahNW;Hu,Kevin;Fish,Lisa;Chen,Yih-An;Allegakoen,Paul;Hui,KelianaSF;Pham,JuliaH;Baco,MariaB;Song,Hanbing;Giacomelli,AndrewO;Vazquez,Francisca;Ghandi,Mahmoud;Goodarzi,Hani;Huang,FranklinW
• 通讯作者: Huang,FranklinW