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; 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（M6A）是哺乳动物细胞中最丰富的mRNA甲基化。新兴证据 在许多癌症中，M6A与癌症表型联系起来，促使研究M6A和 癌症生物学。但是，M6A效应者作家，橡皮图和读者的失调以及重新编程 M6A位点的特征很差。基因表达的M6A调节模式如何介导 下游癌症途径和表型大多缺失。我们已经开发了几种广泛使用的 M6A峰检测，差分M6A分析和M6A目标的功能预测的信息学工具 来自Merip-Seq M6A分析数据。使用这些工具，我们与癌症生物学合作者合作 揭示了由致癌病毒KSHV和 发现了M6A作家，橡皮擦和读者之间的串扰，以调节癌症的生长和进展。 但是，快速移动的M6A和癌症研究构成了许多未满足的信息学挑战。他们之中， 准确识别单基M6A位点并从中预测关键M6A调节机制的能力 分析数据严重缺乏。此外，一个综合数据库，该数据库对位置进行编目和启用查询， 在正常和癌症条件下，M6A甲基化和功能的内容以及如何非常可取。解决 挑战，我们建议开发M6A-Suite，一种信息箱，管道和资源，以促进 M6A在癌症中的机理研究。在M6A套件中开发工具的关键障碍是缺乏大型，高的 高质量的培训数据集。为此，我们收集了1,113个人和680个小鼠Merip-seq 来自癌细胞系，肿瘤和正常组织的样品，并鉴定出> 4M M6A峰。并行，我们有 还收集了194,060个单基M6A位点，在9个细胞系和3个组织中收集。我们建议将这些数据利用 构建高度理想的培训数据集。使用这些数据集，我们将发展高效，准确 Merip-Seq和Nanobore数据的单基M6A检测和量化的工具（AIM 1），启用 M6A介导的RNA衰变和拼接的预测（AIM 2），并建立全面的，可查询的M6A- KB知识基础在广泛的公共Merip-Seq和Nanobore集合中对这些预测进行分类 癌症和正常细胞的数据以及在不同条件下的组织（AIM 3）。我们将系统地测试和 通过该项目中的许多建立和新兴的合作来评估这些工具 在ITCR财团外。我们将使研究社区免费提供工具和数据 不断寻求合作者和用户的反馈以进行改进。考虑到新兴的本质 M6A和癌症研究，将这些工具添加到ITCR计划中将对这一重要的这一重要影响， 快速增长，新的癌症研究领域。