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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要 N6-甲基-腺苷 (m6A) 是哺乳动物细胞中最丰富的 mRNA 甲基化。新出现的证据已将 m6A 与许多癌症的癌症表型联系起来，刺激了 m6A 和癌症生物学。然而，m6A 效应器写入器、擦除器和读取器的失调以及 m6A 位点的表征很差。 m6A 基因表达调节的不同模式如何介导下游癌症途径和表型大多缺失。我们开发了多种广泛使用的用于 m6A 峰值检测、差异 m6A 分析和 m6A 目标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，揭示了受致癌病毒 KSHV 感染的细胞中重新编程的病毒和宿主 m6A 表观转录组，以及发现 m6A 写入器、擦除器和读取器之间的串扰来调节癌症的生长和进展。然而，快速发展的 m6A 和癌症研究带来了许多未满足的信息学挑战。他们之中，能够准确识别单碱基 m6A 位点并预测关键的 m6A 调控机制剖析数据严重缺乏。此外，还有一个综合数据库，可以对位置进行编目并进行查询， m6A 甲基化及其在正常和癌症条件下的功能是什么以及如何变化是非常值得关注的。致地址挑战，我们建议开发 m6A-Suite，一个信息学工具箱、管道和资源，以促进 m6A在癌症中的机制研究。在 m6A-Suite 中开发工具的一个主要障碍是缺乏大型、高质量训练数据集。为此，我们收集了 1,113 份人类和 680 份小鼠 MeRIP-seq 来自癌细胞系、肿瘤和正常组织的样本，并鉴定出 >4M m6A 峰。与此同时，我们有还收集了 9 个细胞系和 3 个组织中的 194,060 个单碱基 m6A 位点。我们建议利用这些数据构建非常理想的训练数据集。使用这些数据集，我们将开发高效、准确的用于从 MeRIP-seq 和纳米孔数据中进行单碱基 m6A 检测和定量的工具（目标 1），使预测 m6A 介导的 RNA 衰减和剪接（目标 2），并建立全面的、可查询的 m6A- 知识库知识库在广泛的公共 MeRIP-seq 和纳米孔集合中对这些预测进行编目不同条件下的癌症和正常细胞以及组织的数据（目标 3）。我们将系统地测试和在该项目中以及通过内部和新兴的许多已建立的和新兴的合作来评估这些工具 ITCR 联盟之外。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进行改进。鉴于新兴的性质 m6A 和癌症研究，将这些工具添加到 ITCR 计划将对这一重要的、快速发展的癌症研究新领域。