Deciphering the Regulatory Role of Small RNAs on Alternative Splicing

解读小 RNA 对选择性剪接的调节作用

• 批准号: 9331728
• 负责人: PING MA
• 金额: $ 32.55万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9331728
• 关键词: Address; Aging; Alternative Splicing; Analysis of Variance; Area; Biological Process; Biology; Chromatin Structure; Code; Data; Disease; Eukaryota; Exons; Gene Chips; Genes; Goals; Heart Diseases; Human; Instruction; Intervention; Introns; Joints; Knowledge; Malignant Neoplasms; Messenger RNA; Methods; Modeling; Play; Protein Isoforms; Proteins; Proteomics; RNA; RNA Splicing; RNA analysis; Research; Role; Small Interfering RNA; Small RNA; Spices; Statistical Methods; Testing; Transcript; Untranslated RNA; genome-wide; human disease; mRNA Precursor; neurodevelopment; novel; theories; tool; transcriptome sequencing

In higher eukaryotes such as humans, genes are transcribed to pre-mRNAs, in which exons (RNA segments that code for proteins) are separated from each other by intervening introns (RNA segments that do not code for proteins). A gene may generate different mature mRNA transcripts by selectively including different combinations of exons. This biological process is referred to as alternative splicing and is the main strategy for genes to generate proteomic diversity. Extenstive evidences indicate that over 95% of human genes undergo alternative splicing. Aberrant splicing of pre-mRNAs can cause various human diseases, such as cancers, aging related diseases, heart diseases and neuro-development di·seases. Recent studies have shown that small non-coding RNAs play an essential regulatory role in alternative splicing. For example, small interfering RNAs (siRNAs) can regulate alternative splicing by modulating chromatin structure. The overarching goal of this project is to develop a set of novel statistical tools to advance our knowledge of the regulatory role of small RNAs on alternative splicing. More specifically, the invetigators of this project will (1) develop effective significance testing theory and methods via generalized smoothing spline ANOVA models to identify genome-wide small RNA targets; (2) develop a new statistical framework for isoform assembly and quantification via joint modeling multisample RNA-seq data; (3) bridge the research gap in the study of small RNAs by elucidating the regulatory role of small RNAs on isoform expression. Although the proposed methods are developed to address the current analytical challenges in isoform and small RNA analysis, a burgeoning area in biology studies, the statistical theory and methods can be broadly applied to many research fields.

在高等真核生物如人类中，基因被转录为前mRNA，其中外显子（RNA片段）被转录为前mRNA。 编码蛋白质的RNA片段）被插入的内含子（不编码蛋白质的RNA片段）彼此分开。 蛋白质）。基因可以通过选择性地包括不同的mRNA转录物来产生不同的成熟mRNA转录物。 外显子的组合。这种生物学过程被称为选择性剪接，是主要的策略 基因产生蛋白质组多样性。大量证据表明，超过95%的人类基因 进行选择性剪接。前体mRNA的异常剪接可导致多种人类疾病，例如 癌症、衰老相关疾病、心脏病和神经发育疾病。最近的研究 显示小的非编码RNA在选择性剪接中发挥重要的调节作用。比如说， 小干扰RNA（siRNA）可以通过调节染色质结构来调节可变剪接。的 该项目的总体目标是开发一套新颖的统计工具，以促进我们对 小RNA对可变剪接的调节作用。更具体地说，本项目的研究人员将（1） 利用广义光滑样条方差分析模型，发展有效的显著性检验理论和方法 识别全基因组小RNA靶点;（2）开发新的异构体组装统计框架 通过联合建模多样本RNA-seq数据进行定量;（3）弥合研究中的研究空白， 通过阐明小RNA对同种型表达的调节作用来研究小RNA。虽然拟议 方法的开发，以解决目前的分析挑战，在异构体和小RNA分析， 生物学是一个新兴的研究领域，统计学的理论和方法可以广泛地应用于许多领域， 研究领域。