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Transgenic models to investigate imprinted gene expression in somatic tissue

研究体细胞组织中印记基因表达的转基因模型

基本信息

批准号：
8686139
负责人：
Matthias Stadtfeld
金额：
$ 16.95万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-24 至 2015-09-23
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8686139
关键词：
Address Adult Alleles Animal Model Animals Applications Grants Biological Models Biopsy Cell Culture Techniques Cells Chromatin Chromosomes Complement Complementary DNA DNA Data Derivation procedure Development Developmental Process Disease Disease Progression Epigenetic Process Event Exhibits Fibroblasts Gametogenesis Gene Expression Gene Targeting Genes Genomic Imprinting Goals Homeostasis Human Hypermethylation Imagery In Vitro Inherited Kidney Laboratories Lead Life Light Maintenance Malignant - descriptor Malignant Neoplasms Mammals Mediating Modeling Molecular Mus Myelogenous Organ Output Physiological Play Positioning Attribute Property Regulation Reporter Reporter Genes Reporting Role Somatic Cell Syndrome System Technology Therapeutic Intervention Tissues Transgenic Animals Transgenic Model Transgenic Organisms Work base design developmental disease embryonic stem cell human disease imprint in vivo induced pluripotent stem cell innovation novel prevent progenitor public health relevance recombinase sex stem therapy design tool

项目摘要

DESCRIPTION (provided by applicant): The epigenetic control of gene expression is central to many developmental processes and plays a pivotal role in the onset and progression of disease. Genomic imprinting, the monoallelic expression of a subset of mammalian genes from either the maternally or the paternally inherited chromosome, is a paradigm of epigenetic regulation. Mediated by sex-specific chromatin marks established during gametogenesis, the expression status of imprinted alleles is believed to be stable in adult tissues. However, loss of imprinting is a hallmark of different cancers and is also frequently observed upon reprogramming somatic cells into induced pluripotent stem (iPS) cells. This raises a number of important questions that have not been addressed. Is loss of imprinting always a pathological event and what are the properties of adult cells expressing imprinted genes? What are the molecules responsible for the maintenance and loss of imprinting? To address these questions, my laboratory is developing animal models that will allow to directly visualize the expression status of two imprinted genes with relevance for human disease at the single-cell level and to trace the developmental output of cells exhibiting loss of imprinting at these loci. This will revel the extent of imprint instability in healthy adult organs and the contribution of cells expressing imprinted genes to steady-state tissue maintenance. In parallel, we will use iPS cell reprogramming as an in vitro system to identify novel components of the imprinting machinery. Together, our studies will shed new light on the little explored role of genomic imprinting in the adult and may aid the therapeutic intervention of diseases characterized by imprinted gene dysregulation.

描述（由申请人提供）：基因表达的表观遗传控制是许多发育过程的核心，在疾病的发生和进展中起着关键作用。基因组印记是来自母系或父系遗传染色体的哺乳动物基因子集的单等位基因表达，是表观遗传调节的一种范式。在配子发生过程中建立的性别特异性染色质标记介导下，印迹等位基因的表达状态被认为在成体组织中是稳定的。然而，印记的丧失是不同癌症的标志，并且在将体细胞重编程为诱导多能干（iPS）细胞时也经常观察到。这就提出了一些尚未解决的重要问题。印记的丧失是否总是一种病理事件？表达印记基因的成体细胞的特性是什么？什么分子负责维持和丧失印记？为了解决这些问题，我的实验室正在开发动物模型，这将允许直接可视化的表达状态的两个印记基因与人类疾病相关的单细胞水平，并跟踪在这些位点表现出印记损失的细胞的发育输出。这将揭示健康成人器官中印记不稳定的程度以及表达印记基因的细胞对稳态组织维持的贡献。同时，我们将使用iPS细胞重编程作为体外系统，以确定新的印记机制的组成部分。总之，我们的研究将揭示新的光在成人基因组印迹的作用很少探索，并可能有助于以印迹基因失调为特征的疾病的治疗干预。