Transgenic models to investigate imprinted gene expression in somatic tissue

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，在疾病的发生和发展中起着关键作用。基因组印记是一种单等位基因的表达，来自母系或父系遗传的染色体，是一种表观遗传调控的范例。在配子体形成过程中建立的性别特异性染色质标记介导下，印迹等位基因在成年组织中的表达状态被认为是稳定的。然而，印迹丢失是不同癌症的一个标志，在体细胞重编程为诱导多能干细胞（iPS）时也经常观察到印迹丢失。这就提出了一些尚未解决的重要问题。印迹的丧失是否总是一种病理事件？表达印迹基因的成年细胞有哪些特性？哪些分子负责印痕的维持和丢失？为了解决这些问题，我的实验室正在开发动物模型，以便在单细胞水平上直接可视化与人类疾病相关的两个印迹基因的表达状态，并追踪在这些基因座上表现出印迹缺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性的程度，以及表达印记基因的细胞对组织维持稳态的贡献。同时，我们将使用iPS细胞重编程作为体外系统来识别印迹机制的新组件。总之，我们的研究将揭示基因组印迹在成人中很少被探索的作用，并可能有助于以印迹基因失调为特征的疾病的治疗干预。

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.