m6A-suite: an informatics pipeline and resource for elucidating roles of m6A epitranscriptome in cancer

m6A-suite：用于阐明 m6A 表观转录组在癌症中的作用的信息学管道和资源

• 批准号: 10645584
• 负责人: Yufei Huang
• 金额: $ 40.86万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-11 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10645584
• 关键词: Acceleration; Address; Algorithms; Alternative Splicing; Area; Cancer Biology; Cancer cell line; Catalogs; Cell Line; Cells; Collaborations; Collection; Communities; Consumption; Data; Data Set; Databases; Detection; Drug Targeting; Ensure; Feedback; Gene Expression; Gene Expression Regulation; Growth; Human; Human Herpesvirus 8; In Vitro; Informatics; Knowledge; Link; Malignant Neoplasms; Mammalian Cell; Maps; Mediating; Messenger RNA; Metabolism; Methylation; Modality; Modeling; Modification; Mus; Nature; Normal Cell; Normal tissue morphology; Oncogenic Viruses; Oncologist; Pathway interactions; Pattern; Performance; Phenotype; Physiological Processes; Play; Proteins; RNA; RNA Decay; RNA Splicing; Reader; Research; Resolution; Resources; Role; Sampling; Shapes; Signal Transduction; Site; Testing; Therapeutic; Tissues; Training; Tumor Tissue; Viral; Work; algorithm training; anticancer research; base; biomarker identification; cancer cell; design; differential expression; epitranscriptome; improved; in vivo; informatics tool; insight; knowledgebase; mRNA Decay; mRNA Stability; multimodality; nanopore; open data; open source; predictive tools; programs; sequence learning; therapeutic biomarker; tool; usability

Project Summary N6-methyl-adenosine (m6A) is the most abundant mRNA methylation in mammalian cells. Emerging evidence has linked m6A with cancer phenotypes in many cancers, spurring a surge of research in studying m6A and cancer biology. However, dysregulation of m6A effector writers, erasers, and readers and reprogramming of m6A sites are poorly characterized. How different modes of m6A-regulation of gene expression mediate the downstream cancer pathways and phenotypes is mostly missing. We have developed several widely used informatics tools for m6A peak detection, differential m6A analysis, and functional predictions for m6A targets from MeRIP-seq m6A profiling data. Using these tools, we worked together with cancer biology collaborators to reveal reprogramed viral and host m6A epitranscriptome in cells infected by the oncogenic virus KSHV and discovered a cross-talk between m6A writers, erasers, and readers to regulate cancer growth and progression. However, the fast-moving m6A and cancer research poses many unmet informatics challenges. Among them, the ability to accurately identify single-base m6A sites and predict key m6A regulatory mechanisms from profiling data is seriously lacking. Also, a comprehensive database that catalogs and enables queries of where, what, and how of m6A methylation and function in normal and cancer conditions is highly desirable. To address challenges, we propose to develop m6A-Suite, an informatics toolbox, pipeline, and resources to facilitate the mechanistic study of m6A in cancer. A key obstacle to developing tools in m6A-Suite is a lack of large, high- quality training datasets. Toward this end, we have collected 1,113 human and 680 mouse MeRIP-seq samples from cancer cell lines, tumors, and normal tissues and identified >4M m6A peaks. In parallel, we have also collected 194,060 single-base m6A sites in 9 cell lines and 3 tissues. We propose to leverage this data to construct the highly desirable training datasets. Using these datasets, we will develop efficient and accurate tools for single-base m6A detection and quantification from MeRIP-seq and nanopore data (Aim 1), enable the prediction of m6A-mediated RNA decay and splicing (Aim 2), and establish the comprehensive, queriable m6A- KB knowledgbase to catalog these predictions in an extensive collection of public MeRIP-seq and nanopore data in cancer and normal cells, and tissues in diverse conditions(Aim 3). We will systematically test and evaluate these tools within this project and through many established and emerging collaborations inside and outside the ITCR consortium. We will make the tools and data freely available to the research community and constantly seek feedback from the collaborators and users for improvement. Given the emerging nature of m6A and cancer research, the addition of these tools to the ITCR program will positively impact this important, fast-growing, new area of cancer research.

项目摘要 N6-甲基腺苷（m6 A）是哺乳动物细胞中最丰富的mRNA甲基化。新出现的证据 将m6 A与许多癌症的癌症表型联系起来，刺激了研究m6 A的研究热潮， 癌症生物学然而，m6 A效应器写入器、擦除器和读取器的调节异常以及m6 A效应器的重编程是可能的。 m6 A位点的特征不明显。不同的m6 A基因表达调控模式如何介导 下游癌症途径和表型大多缺失。我们开发了几种广泛使用的 用于m6 A峰值检测、差异m6 A分析和m6 A靶点功能预测的信息学工具 来自MeRIP-seq m6 A分析数据。使用这些工具，我们与癌症生物学合作者一起工作， 揭示了在被致癌病毒KSHV感染的细胞中重编程的病毒和宿主m6 A表位组， 发现了m6 A写入器、擦除器和读取器之间的相互作用，以调节癌症的生长和进展。 然而，快速发展的m6 A和癌症研究提出了许多未满足的信息学挑战。其中， 准确鉴定单碱基m6 A位点和预测关键m6 A调控机制的能力， 分析数据严重缺乏。此外，一个全面的数据库，目录，并使查询的地方， m6 A甲基化和功能在正常和癌症条件下是什么以及如何是非常令人期望的。解决 挑战，我们建议开发m6 A套件，一个信息学工具箱，管道和资源，以促进 m6 A在癌症中的机制研究。在m6 A-Suite中开发工具的一个关键障碍是缺乏大型、高性能的 高质量的训练数据。为此，我们收集了1，113个人和680只小鼠MeRIP-seq 来自癌细胞系、肿瘤和正常组织的样本，并识别出> 4 M m6 A峰。同时，我们有 还在9个细胞系和3个组织中收集了194，060个单碱基m6 A位点。我们建议利用这些数据， 构建高度期望的训练数据集。利用这些数据集，我们将开发高效、准确的 用于从MeRIP-seq和纳米孔数据（Aim 1）进行单碱基m6 A检测和定量的工具，使得能够 预测m6 A介导的RNA衰变和剪接（目标2），并建立全面的，可查询的m6 A- KB知识库将这些预测编入公共MeRIP-seq和纳米孔的广泛集合中 癌症和正常细胞以及不同条件下的组织的数据（目标3）。我们将系统地测试和 在本项目中以及通过内部许多已建立和新兴的合作来评估这些工具， 在ITCR财团之外。我们将向研究界免费提供工具和数据， 不断寻求合作者和用户的反馈，以便改进。鉴于新出现的 m6 A和癌症研究，将这些工具添加到ITCR计划将积极影响这一重要， 快速发展的癌症研究新领域