Chromatin-based mechanisms of dynamic gene expression/repression

基于染色质的动态基因表达/抑制机制

• 批准号: 211400705
• 负责人: Professor Dr. Tilman Borggrefe
• 金额: --
• 依托单位: Biochemisches Institut
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/211400705?language=en
• 关键词: Chromatin; based; mechanisms; dynamic; gene

Our laboratory focuses on chromatin-based mechanisms of gene regulation by the conserved Notch signaling pathway. Upon ligand binding, the nuclear factor RBP-J activates transcription of target genes whereas in the absence of signaling, RBP-J switches off target gene expression by assembling a corepressor complex. Recently, we have biochemically and functionally characterized several key components of the corepressor complex. Here, we propose to further characterize the coactivator complex and a histonemethyltransferase complex that keeps target genes ‘responsive’ (AIM 1). We will define the chromatin context at Notch target genes throughout the genome and gain insights into the molecular mechanisms at selected promoters (AIM 2). Finally, combining the data provided by the genome-wide analysis together with an unbiased functional genomic approach (RNAi screen), we will assess impact of novel chromatin modifiers on target genes (AIM 3). The successful execution of this project would significantly advance our understanding of chromatin-based mechanisms of gene regulation by signal transduction pathways and may help to discover novel therapeutic targets for Notch-associated diseases.

我们的实验室专注于基于染色质的基因调控机制，通过保守的Notch信号通路。在配体结合后，核因子RBP-J激活靶基因的转录，而在缺乏信号传导的情况下，RBP-J通过组装一个辅抑制因子复合物来关闭靶基因的表达。最近，我们对辅抑制因子复合物的几个关键成分进行了生化和功能表征。在这里，我们建议进一步表征共激活子复合物和组甲基转移酶复合物，以保持靶基因的“反应”（AIM 1）。我们将在整个基因组中定义Notch靶基因的染色质背景，并深入了解选定启动子的分子机制（AIM 2）。最后，结合全基因组分析提供的数据以及无偏倚的功能基因组方法（RNAi筛选），我们将评估新型染色质修饰剂对靶基因的影响（AIM 3）。该项目的成功实施将极大地促进我们对染色质基因信号转导调控机制的理解，并可能有助于发现notch相关疾病的新治疗靶点。

项目成果

The Tumor Suppressor Ikaros Shapes the Repertoire of Notch Target Genes in T Cells

• DOI: 10.1126/scisignal.2004545
• 发表时间: 2014-03-18
• 期刊: SCIENCE SIGNALING
• 影响因子: 7.3
• 作者: Geimer Le Lay, Anne-Solen;Oravecz, Attila;Chan, Susan
• 通讯作者: Chan, Susan

Site-specific methylation of Notch1 controls the amplitude and duration of the Notch1 response

• DOI: 10.1126/scisignal.2005892
• 发表时间: 2015-03-24
• 期刊: SCIENCE SIGNALING
• 影响因子: 7.3
• 作者: Hein, Kerstin;Mittler, Gerhard;Borggrefe, Tilman
• 通讯作者: Borggrefe, Tilman