Identification and characterization of functional modules in Lef/Tcf

Lef/Tcf 中功能模块的识别和表征

• 批准号: 88429810
• 负责人: Dr. Dietmar Gradl
• 金额: --
• 依托单位: Abteilung für Zell- und Entwicklungsbiologie
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2009
• 资助国家: 德国
• 起止时间: 2008-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/88429810?language=en
• 关键词: Identification; characterization; functional; modules; Lef

In the previous years we confirmed our hypothesis that individual Lef/Tcf family members regulate the cell-type specific response to canonical wnt-signaling. Meanwhile, it is widely accepted that the “classical view” to simply unite Lef/Tcf transcription factors as nuclear transducer of the wnt/b-catenin pathway ignores many aspects of cell- and tissue specific responses. Although we identified Hic-5 (Ghogomu et al., 2006) as novel subtype specific binding partner, many aspects of subtype specific target gene regulation remain unanswered. Similarly, other novel Tcf-binding partners including HIC1, HBP and PIAS explain the subtype-specificity only partially. Instead, novel results indicate epigenetic mechanisms as major regulatory principle for Tcf-subtype-, promoter- and cell-type specific regulation. With the identification of Xcirp as XTcf-3 specific target gene, the regulation of XTcf-4 via a Lef/Tcf binding site on its promoter and by including additional direct wnt target genes we have now the tools in our hands for a systematic analysis of epigenetic mechanisms for Tcf subtype specific target gene regulation.From an evolutionary point of view, it is interesting that evertebrates express only one Tcf while vertebrates express four Lef/Tcfs. Our previous analyses on Tcf-subtype specific functions in Xenopus allows us now to assign at least one specific aspect in early embryogenesis to one distinct Lef/Tcf family member. Thus, in reconstitution experiments we will be able to allocate ancient Lef/Tcf functions. This approach will help us to identify regions/domains important for the distinct functions. These domains shall be further characterized.

在过去的几年中，我们证实了我们的假设，即个别Lef/Tcf家族成员调节典型wnt信号传导的细胞类型特异性反应。同时，人们普遍认为，简单地将Lef/Tcf转录因子联合起来作为wnt/β-连环蛋白途径的核转导子的“经典观点”忽略了细胞和组织特异性反应的许多方面。虽然我们鉴定了Hic-5（Ghogomu等人，2006）作为新型亚型特异性结合伴侣，亚型特异性靶基因调控的许多方面仍然没有答案。类似地，其他新的Tcf结合配偶体，包括TCF 1、HBP和皮亚斯，仅部分解释了亚型特异性。相反，新的结果表明表观遗传机制作为Tcf亚型，启动子和细胞类型特异性调控的主要调控原则。随着Xcirp作为XTcf-3特异性靶基因的鉴定，XTcf-4通过其启动子上的Lef/Tcf结合位点的调控以及通过包括额外的直接wnt靶基因，我们现在掌握了用于系统分析Tcf亚型特异性靶基因调控的表观遗传机制的工具。有趣是，无脊椎动物仅表达一种Tcf，而脊椎动物表达四种Lef/Tcf。我们以前的分析Tcf亚型在非洲爪蟾特异性功能，现在允许我们分配至少一个特定的方面，在早期胚胎发育到一个不同的Lef/Tcf家族成员。因此，在重建实验中，我们将能够分配古老的Lef/Tcf功能。这种方法将帮助我们识别对不同功能重要的区域/域。这些领域将进一步表征。