表观遗传因子对大鼠生命周期中多器官基因表达的影响

The expression and modification profiles of genes and genomes in different developmental stages and organs constitute the essential molecular basis during the life span of higher organisms and is the focus of functional genomics research. We recently performed RNA-Seq deep sequencing of 320 samples from 11 organs of both sexes of juvenile, adolescent, adult, and aged F344 rats, and constructed the most complete rat transcriptomic bodymap (Nature Communications, 2014). To better understand the spatial-temporal (i.e. organ-age interactions) characteristics in the gene-regulation process of rat, we propose to (1) construct multi-level bodymaps based on the existing massive high-throughput genomic data including RNA-Seq, miRNA-Seq, and DNA methylation; (2) identify multi-level transcription regulatory interactions based on differential spatial-temporal characteristics and decipher important molecular events involved in the regulation of gene expression by epigenetic factors (miRNA and methylation) during the life span of rat, leading to a rat epigenetic bodymap; (3) validate a subset of important molecular events using molecular experiments and assess the feasibility of the epigenetic bodymap; and (4) finally construct a bodymap database of epigenetic regulation of gene-expression profiles as public resources for researchers. This work can provide deep insights into the gene regulatory mechanisms of epigenetic factors and improve our understanding of the genomic functions of rat leading to a better preclinical model for drug development and to better extrapolation to humans.

基因及基因组在不同年龄阶段不同器官中的表达与修饰状态是高等生物生命进程生长发育与衰老的分子基础，也是功能基因组学研究的基本内容。申请人最近通过对来自幼年、青春期、成年及老年的大鼠进行涵盖2种性别11种器官共320个样本的转录组深度测序，绘制出迄今最完整的大鼠转录组图谱（Nature Communications, 2014）。为深入认识大鼠基因表达调控的时空特征，本项目拟⑴基于自有的海量多层次组学数据，构建转录组、miRNA和DNA甲基化的多层次图谱；⑵鉴定不同时空条件下的多层次转录调控关系，发现甲基化与miRNA影响大鼠生命进程的重要分子事件，构建大鼠表观遗传图谱；⑶针对重要分子事件进行实验验证，评估图谱可靠性与适用性；⑷创建大鼠表观遗传图谱数据库，形成公共研究资源。本项目将为阐明表观遗传因子的基因调控机制、认识大鼠基因组功能以及更好地利用大鼠进行药物研发和临床转化奠定基础。

本项目利用已有的组学数据，通过对来自幼年、青春期、成年及老年的大鼠进行涵盖2种性别11种器官共320个样本的转录组深度测序和miRNA测序，1)研究大鼠miRNA表观遗传表达、转录因子和剪接因子图谱；2)整合数据，基于不同时空条件下的多层次转录调控关系，构建表观遗传因子和基因表达的表观遗传调控图谱；3)挖掘和验证影响大鼠生命历程重要的基因表达和表观调控事件；4)进一步挖掘与药物代谢相关的分子事件，帮助了解药物代谢相关的表达调控机制；5)构建大鼠基因表达数据库，便于数据共享。项目培养博士后、博士和硕士研究生共计11名；发表SCI论文11篇，专著1本，申请专利1项，获得软件著作权5项。本项目完成了既定研究目标和研究任务，为阐明表观遗传因子的基因调控机制、认识大鼠基因组功能以及更好地利用大鼠进行药物研发和临床转化奠定基础。

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