EPIGENETIC REGULATION OF STEM CELL FATE CHOICE

干细胞命运选择的表观遗传调控

基本信息

批准号：
9119835
负责人：
Kai Tan
金额：
$ 37.8万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-09 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9119835
关键词：
Binding Sites Biological Assay Blood Cells Cell Lineage Cell Therapy ChIP-seq Chromatin Computer Simulation Coupled Coupling DNA DNA Methylation DNA Transposable Elements Data Derivation procedure Development Developmental Process Disease EP300 gene Elements Enhancers Epigenetic Process Event Gene Expression Gene Expression Regulation Generations Genes Goals Graph Hematological Disease Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Human body In Vitro Joints Knowledge Location Luciferases Maps Methods Modeling Molecular Mus Pathogenesis Pathway interactions Play Procedures Process Property Protocols documentation RNA Interference Reading Regenerative Medicine Regulator Genes Reporter Role Staging Statistical Models Stem Cell Development Stem cells System Testing Tissues Transcription Coactivator Transcriptional Regulation base chromatin immunoprecipitation chromatin modification combinatorial computerized tools embryonic stem cell epigenetic regulation epigenome gain of function gene discovery genome-wide genomic data hematopoietic stem cell fate histone modification improved insight laboratory experiment loss of function mRNA Expression novel overexpression promoter protein protein interaction stem cell differentiation stem cell fate stem cell fate specification transcription factor

项目摘要

DESCRIPTION (provided by applicant): Epigenetic mechanisms of gene regulation contribute significantly to normal development and disease pathogenesis. Our long-term goal is to understand the epigenetic mechanisms involved in stem cell fate choice, using the development of hematopoietic stem cells (HSCs) from embryonic stem cells (ESCs) as our model. Since HSCs can be derived in vitro by directed differentiation of embryonic stem cells (ESCs), this procedure holds great promise for cell-based therapy of hematological disorders. However, compared to later stages of HSC differentiation that give rise to various blood cell lineages, epigenetic mechanisms controlling HSC fate specification from ESCs are poorly understood, impeding efforts to develop an efficient protocol for in vitro derivation of HSCs. Our preliminary data suggest that dynamic and combinatorial chromatin modifications are critical to this process. This application seeks to obtain a systems-level understanding of epigenetic regulation of HSC fate by coupling wet-lab experiments with computational modeling. Specifically, we propose to understand the dynamic and gene network aspects of epigenetic regulation. To this end, we hypothesize that dynamic combination of chromatin modifications modulates the expression of key regulators of HSC development. First, we will map genome-wide chromatin modifications at different stages of the ESC-to-HSC transition. Second, using computational tools developed in our lab and chromatin state maps, we will predict and experimentally validate regulatory DNA elements acting at different stages of the developmental process. Finally, we will develop a novel computational tool for integrating chromatin state maps with other genomics data to uncover gene pathways controlling HSC fate choice. We believe that these systems-level studies will reveal the basic principles of epigenetic regulation in development. Further, the specific knowledge of epigenetic regulation in HSCs will fill a critical knowledge gap in HSC fate specification.

描述（由申请人提供）：基因调控的表观遗传机制对正常发育和疾病发病机制有显着贡献。我们的长期目标是利用胚胎干细胞 (ESC) 发育为造血干细胞 (HSC) 作为我们的模型，了解干细胞命运选择所涉及的表观遗传机制。由于 HSC 可以通过胚胎干细胞 (ESC) 的定向分化在体外产生，因此该过程对于基于细胞的血液疾病治疗具有广阔的前景。然而，与产生各种血细胞谱系的 HSC 分化后期相比，我们对 ESC 控制 HSC 命运规范的表观遗传机制知之甚少，这阻碍了开发 HSC 体外衍生的有效方案的努力。我们的初步数据表明动态和组合染色质修饰对此过程至关重要。该应用旨在通过将湿实验室实验与计算模型相结合，获得对 HSC 命运的表观遗传调控的系统级理解。具体来说，我们建议了解表观遗传调控的动态和基因网络方面。为此，我们假设染色质修饰的动态组合调节 HSC 发育关键调节因子的表达。首先，我们将绘制 ESC 向 HSC 转变不同阶段的全基因组染色质修饰图谱。其次，利用我们实验室开发的计算工具和染色质状态图，我们将预测并通过实验验证在发育过程的不同阶段发挥作用的调控DNA元件。最后，我们将开发一种新的计算工具，用于将染色质状态图与其他基因组数据整合，以揭示控制 HSC 命运选择的基因途径。我们相信这些系统级研究将揭示发育过程中表观遗传调控的基本原理。此外，HSC 表观遗传调控的具体知识将填补 HSC 命运规范的关键知识空白。