Transcriptional Control of the Mouse aA-crystallin locus

小鼠 aA-晶状体蛋白基因座的转录控制

• 批准号: 8659446
• 负责人: Ales Cvekl
• 金额: $ 53.06万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8659446
• 关键词: Binding Sites; Biological Assay; Blindness; Caring; Cataract; Categories; Cell Differentiation process; Cell Nucleus; Chromatin; Chromatin Structure; Country; Crystalline Lens; Crystallins; DNA Binding; Data; Development; Disease; Distal; Enhancers; Epithelium; Event; FGF2 gene; Failure; Feedback; Fibroblast Growth Factor; Fluorescence; Foundations; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Goals; Health; Human; Intraocular lens implant device; Lens Diseases; Lens Fiber; Life Expectancy; Light; Link; Maps; Massive Parallel Sequencing; Mediating; Medicare; Methods; MicroRNAs; Modeling; Molecular; Molecular Conformation; Mus; Mutation; National Eye Institute; Nuclear; Nuclear Structure; Operative Surgical Procedures; Organelles; Patients; Prevalence; Promoter Regions; Prosencephalon; Proteins; Regulation; Regulator Genes; Regulatory Pathway; Reporter Genes; Research; Senile Cataract; Signal Transduction; Signal Transduction Pathway; Staging; Structural Protein; Structure; Testing; Time; Tissues; Transcription Factor AP-1; Transcriptional Regulation; Transgenic Mice; United States National Institutes of Health; Untranslated Regions; Up-Regulation; Vision; Woman; age related; base; cell type; chromatin immunoprecipitation; congenital cataract; cost; fiber cell; genetic regulatory protein; genome wide association study; genome-wide; improved; in vivo; insight; lens; lens transparency; men; mutant; novel; programs; promoter; public health relevance; reconstruction; three dimensional structure; transcription factor

DESCRIPTION (provided by applicant): The long-term goal of this research program is to elucidate those molecular mechanisms that are essential for ¿A-crystallin (Cryaa) gene expression in the lens, and to unravel general lens regulatory mechanisms that follow similar principles of gene regulation. A loss of Cryaa expression or expression of mutant ¿A-crystallin proteins is not compatible with lens transparency and results in lens opacification. Compromised lens transparency leads to cataract formation, a disease of the lens responsible for nearly half of the cases of blindness worldwide. We have now identified a "core" gene regulatory network (GRN), comprised of Pax6, c-Maf and crystallin genes, which is responsible for lens-specific expression of all crystallin genes. Through the identification of two FGF-responsive regions in c-Maf and Cryaa genes, we can now link FGF signaling, a key lens differentiation signal transduction pathway, with crystallin gene expression. In addition, FGF2 stimulates expression of a small group of microRNAs that targets 3'-UTR of c-Maf. These data suggest that c-Maf expression is underbpositive and negative-feedback FGF- dependent control. A hallmark of tissue-specific GRNs is their spatial localization as "transcriptional factories" within the 3D-structure of lens fiber cell nuclei. This proposal will (1) Determine the molecular functions of th FGF-responsive c-Maf promoter and Cryaa distal enhancer DCR1 followed by genome- wide identification of global FGF-regulated networks in the lens, (2) Establish posttranscriptional regulation of c-Maf through FGF2-dependent miRs, and (3) Examine dynamic changes of chromatin structure in differentiating lens fiber cell nuclei and to identify transcriptional factoies that include the Cryaa locus. These data will lay the foundation for understanding the molecular basis of lens fiber cell differentiation through FGF signaling, action of specific DNA-binding transcription factors, modulatory miRs and their target genes, and 3D-organization of lens fiber cell chromatin.

描述（由申请人提供）：该研究计划的长期目标是阐明晶状体中 ¿A-晶状体蛋白 (Cryaa) 基因表达所必需的分子机制，并阐明遵循类似基因调控原理的一般晶状体调控机制。 Cryaa 表达的丧失或突变体 ¿A-晶状体蛋白的表达与晶状体透明度不相容，并导致晶状体混浊。晶状体透明度受损会导致白内障形成，白内障是一种晶状体疾病，导致近一半的白内障 世界范围内的失明案例。我们现在已经确定了一个“核心”基因调控网络（GRN），由 Pax6、c-Maf 和晶状体蛋白基因组成，负责所有晶状体蛋白基因的晶状体特异性表达。通过鉴定 c-Maf 和 Cryaa 基因中的两个 FGF 响应区域，我们现在可以将 FGF 信号（一种关键的晶状体分化信号转导途径）与晶状体蛋白基因表达联系起来。此外，FGF2 刺激一小群针对 c-Maf 3'-UTR 的 microRNA 的表达。这些数据表明c-Maf 表达低于正反馈和负反馈FGF 依赖性控制。组织特异性 GRN 的一个标志是它们在晶状体纤维细胞核 3D 结构中作为“转录工厂”的空间定位。该提案将 (1) 确定 FGF 响应性 c-Maf 启动子和 Cryaa 远端增强子 DCR1 的分子功能，然后对晶状体中全局 FGF 调节网络进行全基因组鉴定，(2) 通过 FGF2 依赖的 miR 建立 c-Maf 的转录后调节，以及 (3) 检查分化晶状体纤维细胞核中染色质结构的动态变化并识别 包括 Cryaa 基因座的转录因子。这些数据将为通过 FGF 信号传导、特定 DNA 结合转录因子的作用、调节 miR 及其靶基因以及晶状体纤维细胞染色质的 3D 组织了解晶状体纤维细胞分化的分子基础奠定基础。