Collaboration of chromatin remodeling and signaling pathways in pluripotency

多能性中染色质重塑和信号通路的协作

• 批准号: 8973055
• 负责人: Rupa Sridharan
• 金额: $ 29.43万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-10 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8973055
• 关键词: Acute; Affect; Age; Ascorbic Acid; Bioinformatics; Biological Models; Cell physiology; Cells; Chromatin; Chromatin Structure; Collaborations; DNA; DNA Methylation; Data; Degenerative Disorder; Down-Regulation; Embryo; Epigenetic Process; Ethics; Exposure to; Family; Genes; Genomics; Glycogen (Starch) Synthase; Goals; Growth Factor; Histones; Immune; Kinetics; Link; Location; Lysine; Maintenance; Mediating; Methylation; Mitogen-Activated Protein Kinases; Modeling; Molecular; Mutation; Pathway interactions; Patients; Phase; Phosphotransferases; Pluripotent Stem Cells; Population; Probability; Process; Property; Regulator Genes; Repression; Role; Signal Pathway; Signal Transduction; Somatic Cell; Specificity; Staging; Stimulus; System; Testing; Therapeutic; Time; Tissue Donors; Tissues; Transcriptional Activation; Translating; cell type; chromatin remodeling; demethylation; embryonic stem cell; epigenome; gene function; gene repression; genome-wide; histone demethylase; human leukocyte antigen testing; improved; induced pluripotent stem cell; inhibitor/antagonist; insight; novel; overexpression; pluripotency; prevent; public health relevance; regenerative therapy; repaired; response; self-renewal; transcription factor; Acute; Affect; Age; Ascorbic Acid; Bioinformatics; Biological Models; Cell physiology; Cells; Chromatin; Chromatin Structure; Collaborations; DNA; DNA Methylation; Data; Degenerative Disorder; Down-Regulation; Embryo; Epigenetic Process; Ethics; Exposure to; Family; Genes; Genomics; Glycogen (Starch) Synthase; Goals; Growth Factor; Histones; Immune; Kinetics; Link; Location; Lysine; Maintenance; Mediating; Methylation; Mitogen-Activated Protein Kinases; Modeling; Molecular; Mutation; Pathway interactions; Patients; Phase; Phosphotransferases; Pluripotent Stem Cells; Population; Probability; Process; Property; Regulator Genes; Repression; Role; Signal Pathway; Signal Transduction; Somatic Cell; Specificity; Staging; Stimulus; System; Testing; Therapeutic; Time; Tissue Donors; Tissues; Transcriptional Activation; Translating; cell type; chromatin remodeling; demethylation; embryonic stem cell; epigenome; gene function; gene repression; genome-wide; histone demethylase; human leukocyte antigen testing; improved; induced pluripotent stem cell; inhibitor/antagonist; insight; novel; overexpression; pluripotency; prevent; public health relevance; regenerative therapy; repaired; response; self-renewal; transcription factor

 DESCRIPTION (provided by applicant): Pluripotent stem cells (PSCs) have the remarkable properties of self-renewal and the capacity to generate differentiated cell types upon exposure to the correct stimulus. PSCs can be derived from the embryo (embryonic stem cells - ESCs) or by overexpression of transcription factors from somatic cells (induced pluripotent stem cells- iPSCs). The process of reprogramming to the iPSC state is slow- taking about 2-3 weeks to complete and inefficient - with only about a maximum of 5% of the starting population completing the process. The properties of PSCs are maintained extrinsically by controlling signaling pathways that prevent their differentiation. Intrinsically there is an auto regulatory lop of core transcription factors, which interacts with the epigenome to maintain the pluripotent state. While in general it is known that modifying the epigenome impacts reprogramming, how specific chromatin modifiers and signaling pathways mechanistically engage with the pluripotency regulatory network is largely unknown. We have found that in reprogramming intermediates, the combined action of a chromatin regulator and signaling modulator synergistically allowed the acquisition of an iPSC state at a very high efficiency. Using this system we have determined that, temporal erasure of key epigenetic marks occurs concomitant with both the transcriptional activation of pluripotency genes and down regulation of key growth factor signaling genes. In this proposal we will investigate the mechanism of interplay between the epigenome and signaling during the acquisition of pluripotency with the following aims: 1) To elucidate the mechanism of differential contribution of histone demethylases to pluripotency 2) To determine the interdependence of epigenetic marks during the acquisition of pluripotency and 3) To define the mechanistic contribution of gene repression during reprogramming. In this proposal we will gain a significant understanding of the mechanism of reprogramming and the barriers that have to be overcome to reach the iPSC state. This information is essential for expediting the process and increasing the efficiency and will therefore be highly impactful in translating the use of iPSCs for therapeutic purposes.

 描述（由适用提供）：多能干细胞（PSC）具有自我更新的显着特性，并且在暴露于正确刺激的情况下产生分化的细胞类型的能力。 PSC可以源自胚胎（胚胎干细胞 - ESC），也可以通过从体细胞（诱导多能干细胞-IPSC）的转录因子过表达得出。重新编程到IPSC状态的过程缓慢 - 花费大约2-3周才能完成和无效 - 最多只有5％的起始人群完成该过程。 PSC的特性通过控制防止其分化的信号通路外在维持。从本质上讲，核心转录因子的自动调节性LOP与表观基因组相互作用以维持多能状态。通常，众所周知，修改表观组会影响重编程，但特定的染色质修饰符和信号通路如何与多能调节网络机械互动是未知的。我们发现，在重新编程中间体时，染色质调节剂和信号调节器的合并作用可以协同允许以非常高的效率获得IPSC状态。使用该系统，我们确定，关键表观遗传标记的暂时擦除与多能基因的转录激活以及关键生长因子信号基因的调节有关。在该提案中，我们将研究表观遗传组与信号传导之间的相互作用机制，以下目的是：1）阐明组蛋白脱甲基酶对多脂蛋白的差异贡献的机制2）确定在pluripotity和3贡献中的表达过程中表现出依赖性的相互依存关系的相互依存的机制，并在贡献过程中贡献了贡献的机制，并在3次贡献中依赖于贡献的机制。在此提案中，我们将对重编程机理和必须克服的障碍的机理有深入的了解才能达到IPSC状态。该信息对于加快过程并提高效率至关重要，因此对于将IPSC用于治疗目的而言将具有很高的影响。