Groucho co-repressors in the regulation of pancreatic islet development

Groucho 辅阻遏物在胰岛发育调节中的作用

• 批准号: 10180956
• 负责人: Alexandra Theis
• 金额: $ 3.57万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10180956
• 关键词: Affect; Animals; B cell differentiation; B-Cell Development; Beta Cell; Binding; Birth; Blood Glucose; Cell Count; Cell Line; Cell physiology; Cells; ChIP-seq; Characteristics; Chromatin; DNA; Data; Development; Diabetes Mellitus; Disease; Endocrine; Epigenetic Process; Exhibits; Functional disorder; Gene Expression; Gene Expression Regulation; Gene Family; Gene Silencing; Genes; Genetic Transcription; Histone Deacetylase; Hyperglycemia; In Vitro; Insulin; Insulin-Dependent Diabetes Mellitus; Islet Cell; Islets of Langerhans; Knock-out; Knockout Mice; Knowledge; Lead; Mediating; Molecular; Mus; Mutant Strains Mice; Non-Insulin-Dependent Diabetes Mellitus; Pancreas; Phenotype; Process; Proteins; RNA Polymerase II; Regulation; Repression; Research; Role; Structure of beta Cell of islet; System; Testing; Transcriptional Regulation; United States; Up-Regulation; Work; biological systems; cell type; diabetic; effective therapy; endocrine pancreas development; experimental study; gene function; genetic corepressor; in vivo; islet; lipid biosynthesis; postnatal; prevent; programs; recruit; reduce symptoms; transcription factor; transcriptome sequencing; transdifferentiation

Project Summary Loss of insulin-producing β cell number and function, the defining characteristics of Type 1 and Type 2 diabetes (T1D and T2D, respectively), affects over 30 million people in the United States. The cellular mechanisms that lead to this disease remain unknown, although significant research is currently ongoing to understand the development and function of β cells to ultimately advance our knowledge of the disease and generate effective treatments for diabetes. Much of the work in this field has described the transcription factors that are necessary for regulating gene expression during these processes. However, transcription factors do not act alone to regulate gene expression; other factors, such as co-activators and co-repressors, also interact with and influence transcription factor activity to allow activation or repression of target genes. One group of proteins that interact with transcription factors are the Groucho-related gene (GRG) family of co-repressors. GRGs do not bind directly to DNA – instead they are recruited to DNA by an array of transcription factors. GRGs promote repression of target genes by recruiting epigenetic modifiers, such as HDACs, to silence gene expression. Recent studies have shown that the mechanism of GRG-mediated gene regulation may not be this straight-forward and that the function of GRGs differ in cell-to-cell and context-dependent manners. GRGs have been shown to interact with critical pancreas transcription factors in the pancreas and in other biological systems. The interaction of GRG3 with NKX2.2, a pancreas transcription factor, is necessary for β cell development by repressing non-β cell programs. GRGs also interact with other pancreas transcription factors, such as NKX6.1 and PAX6 in other contexts, suggesting that GRGs may modulate activity of multiple transcription factors during β cell development and function. Preliminary data demonstrates that loss of Grg3 in the pancreas results in hyperglycemia and alterations in endocrine cell numbers in mice. Together, these data indicate that GRG3 is important in β cell development and function, although the molecular mechanism of GRGs in these processes is not fully understood. In this proposal, I will elucidate the mechanism of GRG transcriptional activity in the regulation of β cell identity and function using in vivo and in vitro approaches.

项目摘要 产生胰岛素的β细胞数量和功能丧失是1型和2型糖尿病的显著特征 (分别为T1D和T2D)，在美国影响着3000多万人。它的细胞机制 导致这种疾病的原因尚不清楚，尽管目前正在进行重大研究以了解 β细胞的发展和功能最终促进我们对疾病的了解并产生有效的 糖尿病的治疗。这一领域的许多工作都描述了必要的转录因子 在这些过程中调节基因表达。然而，转录因子并不是单独作用于 调节基因表达；其他因素，如共激活物和共抑制物，也相互作用和影响 转录因子激活或抑制靶基因的活性。一组相互作用的蛋白质 与转录因子有关的是Groucho相关基因(GRG)家族的共抑制因子。GRG不直接绑定 DNA--相反，它们被一系列转录因子招募到DNA中。GRG促进对 通过招募表观遗传修饰物(如HDAC)来沉默基因表达来靶向基因。最新研究 已经表明，GRG介导的基因调控机制可能不是这么直接的，而且 GRG的功能在细胞间和上下文相关的方式上有所不同。GRG已经被证明可以与 胰腺和其他生物系统中的关键胰腺转录因子。GRG3的相互作用 NKX2.2是一种胰腺转录因子，通过抑制非β细胞对β细胞的发育是必需的 程序。GRGs还与其他胰腺转录因子相互作用，如在其他 提示GRGs可能在β细胞发育过程中调节多种转录因子的活性 和功能。初步数据显示，胰腺中Grg3的缺失会导致高血糖和 小鼠内分泌细胞数量的变化。综上所述，这些数据表明grg3在β细胞中是重要的 发展和功能，尽管GRGs在这些过程中的分子机制还不完全 明白了。在这项提案中，我将阐明GRG转录活性在调控中的机制 使用体内和体外方法研究β细胞的特性和功能。