Discovery of Novel miRNAs and isomiRs and Use in Sub-typing TCGA Cancers

新型 miRNA 和 isomiR 的发现及其在 TCGA 癌症分型中的应用

基本信息

批准号：
9188070
负责人：
Isidore Rigoutsos
金额：
$ 20.36万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-01 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9188070
关键词：
AIDS diagnosis African American Animal Model Breast Cancer Model Cancer cell line Cause of Death Cells Cessation of life Clinical Data Code Communities Complex Data Data Set Databases Dependence Dependency Development Diagnostic Dimensions Disease Event Gender Genes Genetic Transcription Genomics Heart Diseases Homeostasis Human Human Genome In Vitro Individual Investigation Knowledge Lead Length MCF10A cells MDA-MB-468 Malignant Neoplasms Mediating Messenger RNA MicroRNAs Modeling Molecular Profiling Nature Nucleotides Patients Population Post-Transcriptional Regulation Primates Protein Isoforms RNA Interference Pathway RNA-Induced Silencing Complex Race Reporting Sampling The Cancer Genome Atlas Tissues Transcript Untranslated RNA Ursidae Family Woman arm base cancer diagnosis cancer subtypes cancer therapy cancer type deep sequencing design disorder subtype human tissue improved insight lymphoblastoid cell line malignant breast neoplasm men mouse model new therapeutic target novel novel therapeutic intervention novel therapeutics online resource outcome forecast public health relevance repository targeted treatment therapeutic candidate therapeutic target transcriptome sequencing transcriptomics triple-negative invasive breast carcinoma

项目摘要

DESCRIPTION (provided by applicant): MicroRNAs (miRNAs) are critical players in development and homeostasis and potent post-transcriptional regulators of numerous transcripts. Despite tremendous progress during the last two decades, key questions such as "how many miRNAs are encoded in the human genome," "how many distinct miRNA products arise from a single miRNA locus," and "how many transcripts are targeted by each mature miRNA product" remain largely open. Their answers directly bear upon the community's attempts to unravel and understand the complexity of post-transcriptional regulation in disease. We recently reported our analyses of deep-sequencing transcriptomic data (short RNA-seq) from 1,323 individuals and the discovery of 3,707 novel human miRNAs that are tissue-specific and pri-mate-specific, effectively tripling the number of human miRNA precursors currently in the miRBase repository. We also reported results from a parallel study of short RNA-seq data from 452 healthy in-dividuals where we found that miRNA precursor arms produce multiple isoforms, the isomiRs, and that the isomiRs' abundance profiles have an unexpected dependency on an individual's gender, population, and race. For many of the novel miRNAs and the isomiRs we showed that they are loaded on Argonaute, thus they function in the RNA interference pathway. Lastly, we analyzed breast cancer (BRCA) datasets from "The Cancer Genome Atlas" (TCGA) and showed that these observations ex-tend to and hold true in the disease context as well. These results indicate that many molecules that are active in the post-transcriptional regulatory layer have eluded us, as has their unexpected dependency on disease subtype, gender, population, and race. These molecules and the interactions that they mediate await discovery and characterization. Notably, due to their human-/primate-specific nature, many of the newly discovered novel miRNAs and their targeted effectors are absent from and thus cannot be captured by mouse models of cancer. In this project, we will be expanding our TCGA BRCA analyses to four more TCGA cancers. In each of the four cases, we will seek novel miRNAs, establish isomiR profiles for known and novel miRNAs, and characterize their dependencies on cancer sub-type, gender, and race. Based on our preliminary findings we expect that some of the novel miRNAs to be discovered in these cancers will be tissue-specific and human-specific. This will help generate novel highly specific signatures for these cancers and their sub-types. By including in our analyses long RNA-seq datasets we will model the regulatory effects of miRNAs/isomiRs on their messenger-RNA/lncRNA targets. The project will generate a wealth of knowledge that does not currently exist and which will help pave new avenues of exploration for the community and generate insights that can eventually lead to new therapeutic approaches.

描述（由适用提供）：microRNA（miRNA）是开发和体内稳态的关键参与者，以及许多成绩单的潜在转录后调节器。尽管在过去的二十年中取得了巨大进展，但关键问题，例如“人类基因组中有多少miRNA被编码”，“单个miRNA基因座产生了多少不同的miRNA产物”和“每种成熟的miRNA产物靶向多少转录本”仍然很大程度上开放。他们的回答直接取决于社区揭露和了解疾病转录后调节的复杂性的尝试。我们最近报道了我们对1,323个个体的深层转录组数据（简短RNA-SEQ）的分析，并发现了3,707个新型人类miRNA，这些新型人类miRNA是组织特异性且特异性特异性的，有效地使Mirbase Reposoritor中当前人类miRNA前体的数量增加了三倍。我们还报道了来自452个健康中的短RNA-seq数据并行研究的结果，在该研究中，我们发现miRNA前体臂产生多种同工型，Isomirs，并且Isomirs的抽象曲线对个人的性别，人口和种族具有意外的依赖性。对于许多新型miRNA和Isomirs，我们表明它们是在Argonaute上加载的，因此它们在RNA干扰途径中起作用。最后，我们分析了“癌症基因组图集”（TCGA）的乳腺癌（BRCA）数据集，并表明这些观察结果也易于在疾病环境中实现。这些结果表明，在转录后调节层中活跃的许多分子已经避开了我们，他们对疾病亚型，性别，种群和种族的意外依赖也是如此。这些分子及其介导的相互作用等待发现和表征。值得注意的是，由于其人类/灵长类动物特异性的性质，许多新发现的新型miRNA及其靶向效应都是由癌症的小鼠模型捕获的。在这个项目中，我们将将TCGA BRCA分析扩展到另外四种TCGA癌症。在这四种情况下，我们将寻求新颖的miRNA，为已知和新颖的miRNA建立异构体概况，并表征他们对癌症亚型，性别和种族的依赖性。根据我们的初步发现，我们希望在这些癌症中发现一些新型的miRNA将是组织特异性和人类特异性的。这将有助于为这些癌症及其子类型产生新颖的高度特异性签名。通过在我们的分析中包括长RNA-Seq数据集，我们将对miRNA/Isomirs对其质量RNA/LNCRNA靶标的调节作用进行建模。该项目将产生大量知识，这些知识目前不存在，并有助于为社区铺平新的探索途径，并产生有时会导致新的治疗方法的见解。