Identification of transcription factors and cofactors binding to type 2 diabetes risk variants which modulate allele- and tissue-specific gene expression and phenotypes.

鉴定与 2 型糖尿病风险变异结合的转录因子和辅助因子，调节等位基因和组织特异性基因表达和表型。

• 批准号: 321768878
• 负责人: Professor Dr. Heiko Witt, since 1/2021
• 金额: --
• 依托单位: Universitätsklinik und Poliklinik für Innere Medizin I
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/321768878?language=en
• 关键词: Identification; transcription; factors; cofactors; binding

For types 2 diabetes (T2D) more than 65 genetic risk loci have been identified. Most variants are located in noncoding regions, suggesting that regulatory variants modulating gene expression are major contributors to disease risk. Both, regulatory variants and regulated genes at risk loci with numerous variants in linkage disequilibrium remain elusive in most cases. Moreover, numerous data support tissue- and allele-specific regulation of gene expression, which depends on a highly regulated interaction of transcription factors and cofactors, but the precise mechanisms remain elusive in particular for allele-specific gene regulation. Here, we will find regulatory variants by combining a bioinformatics strategy introduced by our group with public domain epigenomic marks of regulatory regions. Moreover, we will identify both, allele- and tissue-specific transcription factors and cofactors, using a highly efficient proteomics methodology. By diverse approaches, such as reporter- and DNA-binding assays, genome-wide expression profiling and CRISPR genome editing, we will confirm genotype dependent modulation of transcriptional activity, nearby and distant gene regulation by the identified factors. Finally, modulation of disease specific phenotypes will be assessed, such as insulin-sensitivity and insulin-secretion for T2D. We will uncover mechanisms at the TCF7L2 locus, reported to modulate T2D phenotypes in beta-cells, liver and adipose-tissue; and consider analysis at further loci suggested to modulate tissue-specific gene expression such as FTO or TLE1. Our tissue-specific in-depth analysis at risk loci, ranging from identification of regulatory variants, binding protein-complexes, regulated genes and modulated phenotypes may guide identification of previously unknown entry points for personalized intervention.

对于2型糖尿病（T2 D），已经确定了超过65个遗传风险位点。大多数变异位于非编码区，这表明调节基因表达的调控变异是疾病风险的主要贡献者。在大多数情况下，在连锁不平衡中具有许多变体的风险位点处的调节变体和调节基因仍然难以捉摸。此外，许多数据支持基因表达的组织和等位基因特异性调控，这取决于转录因子和辅因子的高度调节的相互作用，但精确的机制仍然难以捉摸，特别是等位基因特异性基因调控。在这里，我们将通过将我们小组引入的生物信息学策略与调控区域的公共域表观基因组标记相结合来发现调控变体。此外，我们将确定两个，等位基因和组织特异性转录因子和辅因子，使用高效的蛋白质组学方法。通过不同的方法，如报告基因和DNA结合测定，全基因组表达谱分析和CRISPR基因组编辑，我们将确认转录活性的基因型依赖性调节，通过所确定的因子进行的近距离和远距离基因调控。最后，将评估疾病特异性表型的调节，例如T2 D的胰岛素敏感性和胰岛素分泌。我们将揭示TCF 7 L2基因座的机制，据报道，TCF 7 L2基因座可调节β细胞、肝脏和脂肪组织中的T2 D表型;并考虑在进一步的基因座进行分析，以调节组织特异性基因表达，如FTO或TLE 1。我们对风险位点的组织特异性深入分析，包括鉴定调控变体、结合蛋白复合物、调控基因和调节表型，可以指导识别以前未知的个性化干预切入点。