Dynamic Nucleosome Signatures in Epigenetic Memory and Cancer Development

表观遗传记忆和癌症发展中的动态核小体特征

• 批准号: 8182400
• 负责人: William Lawrence Kath
• 金额: $ 27.3万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8182400
• 关键词: Affect; Alleles; Animal Model; B-Cell Neoplasm; Back; Behavior; Biological Models; Breast Carcinoma; Cell Culture Techniques; Cell Line; Cell model; Cells; Characteristics; Chromosomal Rearrangement; Code; Computer Simulation; Conditioned Culture Media; DNA; Data; Data Set; Deoxycytidine; Development; Disseminated Malignant Neoplasm; Embryo; Epigenetic Process; Exhibits; Fibroblasts; Gene Chips; Gene Expression; Gene Silencing; Genes; Genetic; Goals; Histones; Human; Infection; Knock-out; MCF7 cell; MLH1 gene; Maintenance; Malignant Epithelial Cell; Malignant Neoplasms; Maps; Mature B-Lymphocyte; Measurement; Memory; Methods; Methylation; Modeling; Modification; Molecular; Molecular Profiling; Multiple Myeloma; Myeloproliferative disease; Nature; Nodal; Nucleosomes; Nude Mice; Oncogenes; Phosphotransferases; Point Mutation; Positioning Attribute; Process; Proteins; Protocols documentation; Recombinants; Regulation; Resolution; Simian virus 40; Stem cells; Stochastic Processes; System; T47D; Telomerase; Tetanus Helper Peptide; Transferase; Translations; Viral Tumor Antigens; Work; Yeasts; base; cancer cell; cell type; demethylation; embryonic stem cell; genetic element; genome-wide; histone modification; homologous recombination; human embryonic stem cell; immortalized cell; induced pluripotent stem cell; inhibitor/antagonist; interest; kidney cell; mutant; network models; overexpression; pluripotency; predictive modeling; programs; promoter; research study; sialosyl-T antigen; small hairpin RNA; stem; theories; tumor; tumorigenic

Increasing evidence indicates that cancer results not only from changes in genetic information; in the form of point mutations, chromosomal rearrangements, gene segment amplification and deletion, but also from changes in epigenetic information. Recent theoretical analyses of epigenetic regulation in a model organism (yeast) show that ideas from the dynamical systems field may explain the stability of epigenetic states and the dynamics of spontaneous changes between them. This project will experimentally define the epigenetic changes resulting from the action of (1) a mutant kinase JAK2V617F, a causative factor in myeloproliferative disease; (2) a defined set of oncogenes that transform normal human cells to cancer cells (T antigen, ras, shRNA PP2a, telomerase); and (3) the changes in state of the MLH1 promoter that accompany gene silencing associated with promoter methylation, and reactivation that is induced by 5-aza-2'-deoxycytidine and is associated with DNA demethylation. We will use this information to develop quantitative predictive models of epigenetic inheritance and switching in these systems, based on a dynamical systems framework.

越来越多的证据表明，癌症不仅是由遗传信息的变化引起的，而且是由遗传信息的变化引起的。形式为 点突变、染色体重排、基因片段扩增和缺失，也来自 表观遗传信息的变化。模式生物表观遗传调控的最新理论分析 （酵母）表明动力系统领域的想法可以解释表观遗传状态的稳定性和 它们之间自发变化的动态。该项目将通过实验定义表观遗传 (1) 突变激酶 JAK2V617F 的作用引起的变化，这是骨髓增殖的致病因素 疾病; (2) 一组确定的致癌基因，可将正常人类细胞转化为癌细胞（T 抗原、ras、 shRNA PP2a、端粒酶）； (3) MLH1启动子伴随基因的状态变化 与启动子甲基化相关的沉默以及由 5-aza-2'-deoxycytidine 诱导的重新激活 并与 DNA 去甲基化有关。我们将利用这些信息来开发定量预测 基于动态系统框架的这些系统中的表观遗传和转换模型。