Quantitative Modeling of MicroRNA:Target Interactions in Cell Fate Transition

MicroRNA的定量建模：细胞命运转换中的靶相互作用 项目摘要 细胞命运转换是生物学中最基本的过程之一。这样的过渡通常被认为是 涉及多个基因的协调作用。MicroRNAs(MiRNAs)，一类丰富的小分子 非编码RNA被认为是细胞命运转移的关键调节因子。然而，完整的 阐明miRNA介导的基因调控一直是一个重大挑战，因此目前 对miRNAs在细胞命运转换过程中的作用和机制的了解有限。 MiRNA主要通过3个ʹ‘中的结合位点识别其信使核糖核酸靶标 未翻译的区域(3个ʹ‘UTRs)。成功的靶向结合会导致mRNA降解和/或 翻译性压抑。MiRNA靶标的调控结果很大程度上受miRNA的影响。 丰度和海绵，这是与目标竞争与miRNA相互作用的RNA。 这两个重要因素，以及无核部位贡献和miRNA的定量模型：靶标 现有的miRNA靶标预测算法完全忽略了相互作用。致信地址 这些算法限制了完全阐明miRNA调节功能的跨学科 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图 转化，并通过下一代测序检测miRNA和mRNA的表达；2)建立 新颖的建模框架，可以解决种子和无籽站点的联合影响，并将 MiRNA丰度和海绵效应用于miRNA的定量建模：靶相互作用；3)预测 诱导多能干细胞命运转移过程中miRNA介导的靶向；4)验证miRNA- 细胞命运转换中的调控靶向和无核位点和miRNA和 海绵丰度；以及5)通过数据库和软件工具传播结果。 该项目将产生用于miRNA定量建模的新模型：能够 解决种子和无核位置、miRNA丰度和海绵的影响。该模型可以是 广泛适用于超越细胞命运转变的背景。该项目还将导致识别 以前未知的miRNA靶向基因，并提供了对miRNA- 细胞命运转换的调控。这项研究将极大地促进对miRNA- 介导人类发育中的基因调控，促进以miRNA为导向的疗法的发展， 并有益于人类健康。

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.