Epigenetic control mechanisms and cell-type-specific responsiveness of Wnt/ß-catenin target genes

Wnt/γ-catenin 靶基因的表观遗传控制机制和细胞类型特异性反应

• 批准号: 70366687
• 负责人: Professor Dr. Andreas Hecht
• 金额: --
• 依托单位: Institut für Molekulare Medizin und Zellforschung
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2008
• 资助国家: 德国
• 起止时间: 2007-12-31 至 2012-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/70366687?language=en
• 关键词: Epigenetic; control; mechanisms; cell; type

During embryonic development the same signal transduction mechanisms are repeatedly used to control a wide variety of differentiation processes. Depending upon cellular context any given signal transduction pathway acts upon only a subset of its potential targets. How is this selectivity achieved? We are using Wnt/β-catenin signaling and its nuclear effectors - β-catenin and the T-cell factors (TCFs) - as a paradigm to investigate this fundamental problem. Previous studies have shown that responsive and non-responsive states of Wnt/β-catenin-regulated genes coincide with characteristic patterns of DNA methylation, histone modifications, and promoter occupancy by TCFs. Therefore, epigenetic mechanisms may be used to separate functionally distinct groups of genes by regulating promoter accessibility for TCFs. The goal of the proposed project is to examine this hypothesis and to test the importance of epigenetic features for cell-type and stage-specific control of Wnt-regulated genes. To gain insight into causal relationships, we will establish temporal profiles of changes in chromatin modifications, TCF occupancy, and Wnt-inducibility which accompany functional transitions of Wnt/β-catenin targets in a cellular differentiation model. An extended characterization of cell-type-specific epigenetic landscapes will be undertaken in a locus-specific and domain-wide manner at Wnt/β-catenin target genes, and interdependencies between the generation of distinct chromatin structural states and promoter occupancy of TCFs will be further examined by analyzing alterations of structural and functional properties in response to depletion of either epigenetic modifiers or TCFs, and when association of TCFs with the promoter regions of stably transfected reporter genes is prevented by binding site mutation.

在胚胎开发过程中，相同的信号转导机制可反复用于控制各种分化过程。根据细胞环境，任何给定的信号转导途径仅作用于其潜在目标的一部分。这种选择性如何达到？我们将Wnt/β-catenin信号传导及其核效应-β-catenin和T细胞因子（TCFS）作为范式来研究这一基本问题。先前的研究表明，Wnt/β-catenin调节的基因的反应性和无反应状态与TCFS的DNA甲基化，组蛋白修饰和启动子占用者的特征模式相吻合。因此，表观遗传机制可通过控制TCF的启动子可访问性来分离功能上不同的基因组。拟议项目的目的是检查这一假设，并测试表观遗传特征对Wnt调节基因的细胞类型和特定阶段的控制的重要性。为了深入了解灾难性关系，我们将建立在细胞分化模型中Wnt/β-catenin靶标的功能过渡的染色质修饰，TCF占用和WNT诱导性变化的临时概况。 An extended characterization of cell-type-specific epigenetic landscapes will be undertaken in a locus-specific and domain-wide manner at Wnt/β-catenin target genes, and interdependencies between the generation of distinct chromatin structural states and promoter occupancy of TCFs will be further examined by analysis alterations of structural and functional properties in response to deployment of either epigenetic modifiers or TCFs,当结合位点突变阻止TCF与稳定翻译报告基因的启动子区域的关联时。