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Center for Mammalian Regulatory Genomics

哺乳动物监管基因组学中心

基本信息

批准号：
8728434
负责人：
Bing Ren
金额：
$ 153万
依托单位：
LUDWIG INSTITUTE FOR CANCER RES LTD
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-21 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8728434
关键词：
Address Adopted Adult Animal Model Applied Research Architecture Basic Science Beryllium Binding Biological Biological Assay Biology Cataloging Catalogs Cell Line Cell Separation Cell model Cells ChIP-seq Chromosome Mapping Collection DNA DNA Methylation Data Data Analyses Data Coordinating Center Data Set Development Disease Elements Embryo Embryonic Development Enhancers Ensure First Pregnancy Trimester Functional RNA Funding Gene Expression Profile Gene Expression Regulation Gene Targeting Generations Genes Genome Components Genomics Goals Histocompatibility Testing Human Human Biology Human Cell Line Human Development Human Genome In Vitro Instruction Investigation Laboratory mice Letters Location Methods Molecular Mus Paper Phase Play Population Production Regulator Genes Regulatory Element Research Research Personnel Resolution Resources Role Sampling Series Staging Techniques Technology Time Tissues Transgenic Mice Transgenic Organisms United States National Institutes of Health Validation Work base cell type chromatin modification computerized tools cost effective embryo tissue epigenome epigenomics experience functional genomics gene function genome sequencing genome-wide human disease human tissue improved in vivo insight large scale production mammalian genome member mouse genome mouse model placental mammal postnatal prenatal programs promoter research study transcription factor transcriptome sequencing

项目摘要

Complete annotation of all functional sequences in the human genome remains a major challenge a decade after its initial sequencing. This pertains in particular to gene regulatory elements, many of which are located far away from their target genes, but play fundamental roles in human biology. Significant progress towards annotation of the gene regulatory architecture has been made in recent years predominantly using cultured human cells. However, large-scale studies in mice, as well as anecdotal examples identified in human studies, have indicated the existence of large populations of gene regulatory sequences with very restricted temporal and tissue-specific activity during mammalian development. Despite their critical importance in human development and disease, this set of regulatory sequences will likely be missed by approaches restricted to cell lines or adult tissues. To fill this gap, the major objective for this U54 application is to generate catalogs of developmentally active gene regulatory sequences using existing high throughput data production pipelines for genomic approaches including ChlP-Seq, MethylC-Seq and RNA-Seq on embryonic tissues. Performing such studies directly on human tissues is not feasible due to limited availability of human embryos at relevant stages of development. We will therefore in this study exploit the laboratory mouse, a widely used animal model that shares a similar embryonic developmental program and gene regulatory architecture with humans. In addition to embryonic development, our studies will also generate a complementary reference dataset from postnatal and adult mice to better understand the dynamics of gene regulation over time. Furthermore, we will assess the biological authenticity of identified regulatory sequences by in-depth functional validation using an established transgenic mouse pipeline. It is anticipated that generation of these datasets will fill a major void in the functional annotation o a mammalian genome and help to complete the catalog of gene regulatory sequences in the human genome.

人类基因组中所有功能序列的完整注释在最初测序十年后仍然是一个重大挑战。这尤其与基因调控元件有关，其中许多元件位于远离其目标基因的位置，但在人类生物学中发挥着基础作用。近年来，在基因调控结构的注释方面取得了重大进展，主要是利用培养的人类细胞。然而，在小鼠身上的大规模研究以及在人类研究中发现的轶事例子表明，在哺乳动物的发育过程中，存在大量具有非常有限的时间和组织特异性活性的基因调控序列。尽管它们在人类发育和疾病中至关重要，但这套调控序列很可能会被局限于细胞系或成人组织的方法所遗漏。为了填补这一空白，U54应用程序的主要目标是使用现有的高通量数据生产管道生成发育活跃的基因调控序列目录，用于基因组方法，包括胚胎组织上的ChlP-Seq、甲基C-Seq和RNA-Seq。由于人类胚胎在相关发育阶段的可获得性有限，直接在人体组织上进行此类研究是不可行的。因此，在这项研究中，我们将利用实验室小鼠，这是一种广泛使用的动物模型，它与人类分享类似的胚胎发育程序和基因调控架构。除了胚胎发育，我们的研究还将生成来自出生后和成年小鼠的补充参考数据集，以更好地了解基因调控随时间的动态变化。此外，我们将使用已建立的转基因小鼠管道，通过深入的功能验证来评估已识别的调控序列的生物真实性。预计这些数据集的产生将填补哺乳动物基因组功能注释的一个主要空白，并有助于完成人类基因组中基因调控序列的目录。