Quantitative Modeling of MicroRNA:Target Interactions in Cell Fate Transition

细胞命运转换中microRNA与靶分子相互作用的定量模型 项目摘要 细胞命运转换是生物学中最基本的过程之一。这种转变通常被认为是 涉及多个基因的协调作用。MicroRNAs（miRNAs）是一类丰富的小分子RNA， 非编码RNA被认为是细胞命运转变的关键调节因子。然而， 阐明miRNA介导的基因调控一直是一个主要的挑战，因此目前的 对miRNAs在细胞命运转换过程中的作用和机制的理解是有限的。 miRNAs主要通过3 ′端的结合位点识别其信使RNA（mRNA）靶点。 非翻译区（3个非翻译区）。成功的靶结合导致mRNA降解和/或 翻译抑制miRNA靶点的调节结果受到miRNA的极大影响 丰度和海绵，它们是与靶竞争与miRNA相互作用的RNA。 这两个重要因素，以及无核位点贡献和miRNA的定量建模：靶向 现有的miRNA靶标预测算法已经完全忽略了这种相互作用。解决 这些算法的局限性完全阐明了miRNA的调控功能，跨学科的 研究小组将1）定量绘制miRNA介导的细胞命运关键调控因子的调控 转换，并通过下一代测序测量miRNA和mRNA表达; 2）开发一种 新的建模框架，可以解决种子和无籽网站的综合影响，并结合 用于miRNA定量建模的miRNA丰度和海绵效应：靶相互作用; 3）预测 诱导多能干细胞命运转变期间miRNA介导的靶向; 4）验证miRNA- 在细胞命运转换中调节靶向，并测试预测无籽位点和miRNA的作用， 海绵丰度; 5）通过数据库和软件工具传播结果。 该项目将产生用于定量建模miRNA的新模型：靶相互作用， 解决种子和无籽位点，miRNA丰度和海绵的影响。该模型可 广泛适用于细胞命运转变之外的情况。该项目还将导致确定 以前未知的miRNA靶向基因，并提供关键的机制见解的miRNA- 调控细胞命运的转变。这项研究将大大促进对miRNA的理解- 在人类发育中介导的基因调控，促进miRNA导向治疗的发展， 有益于人体健康。

Quantitative Modeling of MicroRNA:Target Interactions in Cell Fate Transition Project Summary Cell fate transition is one of the most fundamental processes in biology. Such a transition is often thought to involve the coordinated action of multiple genes. MicroRNAs (miRNAs), an abundant class of small non-coding RNAs, have been postulated as key regulators of cell fate transition. However, complete elucidation of miRNA-mediated gene regulation has been a major challenge, and thus the current understanding of the roles and mechanisms of miRNAs during cell fate transition processes is limited. MiRNAs recognize their messenger RNA (mRNA) targets predominantly through binding sites in the 3ʹ′ untranslated regions (3ʹ′ UTRs). Successful target binding leads to mRNA degradation and/or translational repression. The regulatory outcome on a miRNA target is greatly influenced by the miRNA abundance and sponges, which are RNAs that compete with the target for interaction with the miRNA. These two important factors, and quantitative modeling of seedless site contributions and miRNA:target interactions have been completely ignored by existing miRNA target prediction algorithms. To address these algorithmic limitations for complete elucidation of miRNA regulatory functions, the interdisciplinary research team will 1) quantitatively map miRNA-mediated regulation of key regulators of cell fate transition, and measure miRNA and mRNA expression by next-generation sequencing; 2) develop a novel modeling framework that can address combined effects of seed and seedless sites and incorporate miRNA abundance and sponge effects for quantitative modeling of miRNA:target interactions; 3) predict  miRNA-mediated targeting during induced pluripotent stem cell fate transition; 4) validate miRNA- regulated targeting in cell fate transition and test predicted effects of seedless sites and miRNA and sponge abundance; and 5) disseminate results through database and software tools. This project will result in novel models for quantitative modeling of miRNA:target interactions that can address the effects of both seed and seedless sites, miRNA abundance and sponges. The model can be broadly applicable beyond the context of cell fate transition. The project will also lead to the identification of previously unknown miRNA-targeted genes, and provide key mechanistic insights into the miRNA- regulated control of cell fate transition. This research will significantly advance understanding of miRNA- mediated gene regulation in human development, facilitate development of miRNA-oriented therapeutics, and benefit human health.