TISSUE-SPECIFIC MECHANISMS OF EOMESODERMIN-MEDIATED TRANSCRIPTIONAL REGULATION

中胚层介导的转录调控的组织特异性机制

• 批准号: 8718437
• 负责人: Christopher E Slagle
• 金额: $ 5.33万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2015-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8718437
• 关键词: Activins; Animal Model; Animals; Binding; Binding Sites; Biochemical; Boxing; Cardiac; Cell Maturation; Cell physiology; Cells; Characteristics; Colorectal Cancer; Complex; Congenital Heart Defects; Coupled; Craniofacial Abnormalities; Cytotoxic T-Lymphocytes; DNA Binding Domain; Deformity; Development; Developmental Process; Diploidy; Disease; Embryo; Embryonic Development; Endoderm; Family; Family member; Fertility; Foundations; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Models; Genomics; Goals; Human; Immune; Immune system; Immunoprecipitation; Knock-out; Ligands; Limb structure; Link; Lymphoma; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Mesoderm; Microcephaly; Modeling; Morphogenesis; Mus; Mutate; Mutation; Neurons; Nodal; Organ; Pattern; Physiological; Population; Prosencephalon; Proteins; Proteomics; RNA Splicing; Rana; Relative (related person); Research; Risk Factors; Role; Signal Pathway; Signal Transduction; Site; Specificity; Staging; Systems Development; Technology; Tertiary Protein Structure; Tissues; Transcript; Transcriptional Regulation; Transforming Growth Factor beta; Translations; Variant; Work; Xenopus; Xenopus laevis; Zinc Fingers; base; cancer type; cell type; clinically relevant; cofactor; craniofacial; developmental disease; domain mapping; human disease; in vivo; in vivo Model; loss of function; malformation; member; migration; mutant; novel; nuclease; prevent; progenitor; programs; protein protein interaction; public health relevance; research study; therapeutic target; transcription factor

Abstract The T-box family of transcription factors is a group of proteins that regulate a host of developmental processes, such as tissue specification and migration, organ patterning and morphogenesis, and limb identity and outgrowth. Loss of T-box factor function is linked to a wide variety of developmental disorders, including congenital heart defects, craniofacial deformities, and limb malformations, as well as several types of cancer. Eomesodermin (Eomes), a member of the T-box family, is itself associated with a variety of disease states, such as microcephaly, lymphoma, and colorectal cancer. During embryonic development, Eomes is required in a TGF-¿ signaling-associated manner for the earliest stages of vertebrate mesoderm and endoderm specification. Recently, Eomes was shown to directly activate Mesp1, a gene believed to be the master regulator of the cardiogenic transcriptional program, and may do so independently of TGF-¿ signaling. In contrast, Eomes is also required in different tissue contexts for proper forebrain and immune system development. Therefore, Eomes' functional specificity relies not only on the tissue-specific targets it regulates in a given cell, but on the transcriptional co-regulators with which it interacts. I am using an immunoprecipitation-based proteomic approach coupled with biochemical assessment to study the compositions of Eomes- containing transcriptional complexes during early tissue specification. I am also developing in vivo Eomes loss-of-function models in two species of frog, Xenopus laevis and Xenopus tropicalis, to investigate the endogenous functions of Eomes during embryonic development. This work will serve to identify novel coregulators that contribute to Eomes' tissue-specific functions in the developing endoderm and cardiac mesoderm. It will also serve as a foundation for use in identifying novel mechanistic and therapeutic targets for diseases previously associated with loss of Eomes functionality, including immune deficiencies and lymphomas, and potentially congenital heart defects.

摘要 T-box转录因子家族是一组蛋白质，调节一系列 发育过程，如组织指定和迁移、器官构型和 形态发生、肢体识别和生长。T-box因数功能的丧失与 各种各样的发育障碍，包括先天性心脏缺陷、颅面部 畸形、肢体畸形以及几种类型的癌症。常见病 (Eome)是T-box家族的一员，它本身与多种疾病状态有关， 例如小头症、淋巴瘤和结直肠癌。在胚胎发育过程中， 在脊椎动物的早期阶段，eOMES以一种与转化生长因子相关的信号传递方式是必需的 中胚层和内胚层规格。最近，eome被证明可以直接激活Mesp1， 一种被认为是心源性转录程序的主要调节者的基因，可能 这样做不依赖于转化生长因子-β信号。相反，在不同的组织中也需要eome 正常的前脑和免疫系统发育的环境。因此，伊奥姆斯的功能 特异性不仅取决于它在给定细胞中调节的组织特异性靶点，而且还取决于 与之相互作用的转录协同调节因子。我正在使用一种基于免疫沉淀的 蛋白质组学方法结合生化分析研究Eome的组成 在早期组织指定期间包含转录复合体。我也在发展中 两种非洲爪蛙体内功能丧失模型的建立 探讨Eome在胚胎发育过程中的内源性功能。 这项工作将有助于识别有助于eOMES组织特异性的新的协同调节因子 在发育中的内胚层和心脏中胚层中的作用。它还将作为一个基础 用于确定疾病的新机制和治疗靶点 与Eome功能丧失有关，包括免疫缺陷和淋巴瘤，以及 潜在的先天性心脏缺陷。