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

基本信息

批准号：
10225525
负责人：
Rupa Sridharan
金额：
$ 32.19万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-10 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10225525
关键词：
ATAC-seq Ascorbic Acid Bar Codes Biological Models Cell Cycle Cell Differentiation process Cell Lineage Cell physiology Cells Chromatin Chromatin Remodeling Factor Collaborations Cues Data Development Disease Down-Regulation E-Cadherin Embryo Epigenetic Process Epithelial Ethics Event Fibroblasts Funding Gene Expression Gene Expression Profile Genes Genetic Transcription Germ Layers Glycogen (Starch) Synthase Histones Human Immune Individual Injury Kinetics Libraries Masks Mass Spectrum Analysis Mediator of activation protein Mesenchymal Mesoderm Methylation Mitogen-Activated Protein Kinases Modeling Modification Organism Patients Pattern Phosphotransferases Population Population Study Process Property Proteins Route Signal Pathway Signal Transduction Somatic Cell Stimulus System Testing Totipotent cell Translating cell type chromatin remodeling defined contribution embryo cell embryonic stem cell epigenome histone demethylase histone modification improved induced pluripotent stem cell inhibitor/antagonist insight keratinocyte pluripotency population based programs regenerative therapy replacement tissue response stem cell therapy stem-like cell transcription factor transcriptome sequencing transcriptomics

项目摘要

ABSTRACT Functional specialization in a multicellular organism arises when cell fate is established by a specific gene expression pattern. During development from a totipotent cell this is accomplished by the synthesis of spatial and signaling cues that result in epigenetic modifications to elicit unipotent gene expression. Once established, such gene expression patterns are stable unless disrupted by disease or injury. Remarkably the over expression of a few proteins can result in reprogramming of an established cell fate to generate induced pluripotent stem cells (iPSCs) that have the potential to develop into any of the cells of an embryo just like embryonic stem cells (ESCs). iPSCs are the ideal starting point for regenerative therapy since they overcome the ethical and practical concerns of using ESCs. Thus reprogramming provides an ideal model system to mechanistically define cell identity safeguards. However a critical barrier to studying reprogramming is the low efficiency (~3%) and differential kinetics (2-3 weeks) of obtaining iPSCs, so that heterogeneous transcriptional changes are masked in population based studies. We have generated a high efficiency system that combines epigenetic and signaling regulators. Using this system, in this proposal we will determine the most parsimonious route of reprogramming to iPSCs and elucidate the chromatin transitions in cells that become reprogrammed.

抽象的当细胞命运由特定基因确定时，多细胞生物体中的功能专门化就会出现表达模式。在全能细胞的发育过程中，这是通过空间合成来完成的以及导致表观遗传修饰以引发单能基因表达的信号线索。一旦成立，这些基因表达模式是稳定的，除非被疾病或损伤破坏。引人注目的是结束了一些蛋白质的表达可以导致已确定的细胞命运的重新编程，从而产生诱导的细胞命运。多能干细胞（iPSC）有潜力发育成胚胎的任何细胞，就像胚胎干细胞（ESC）。 iPSC 是再生治疗的理想起点，因为它们克服了使用 ESC 的伦理和实际问题。因此，重编程提供了一个理想的模型系统机械地定义细胞身份保护措施。然而，研究重编程的一个关键障碍是低获得 iPSC 的效率（~3%）和差异动力学（2-3 周），从而使异质转录基于人群的研究掩盖了变化。我们已经建立了一个高效的系统，结合了表观遗传和信号调节因子。使用这个系统，在这个提案中我们将确定最重编程 iPSC 的简约途径并阐明细胞中的染色质转变重新编程。