SWI/SNF & Yolk Sac Development

SWI/SNF

• 批准号: 7895065
• 负责人: TERRY R MAGNUSON
• 金额: $ 36.74万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7895065
• 关键词: ATP phosphohydrolase; Adopted; Affect; Amino Acids; Apoptosis; Binding; Biochemical; Blood Vessels; Cadherins; Catalytic Domain; Cells; Chromatin; Chromatin Remodeling Factor; Chromatin Structure; Complementary DNA; Complex; DNA Binding Domain; DNA-dependent ATPase; Data; Defect; Development; Down-Regulation; Drosophila genus; Embryo; Endothelial Cells; Enhancers; Ethylnitrosourea; Event; Evolution; Exhibits; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Transcription; Glycine; Hematopoietic; Histocompatibility Testing; Histones; Human; Lower Organism; Mammals; Mediating; Molecular; Molecular Conformation; Morphogenesis; Mus; Mutate; Mutation; Mutation Analysis; Nature; Nucleosomes; Pathway interactions; Phenotype; Play; Point Mutation; Positioning Attribute; Production; Property; Proteins; Recruitment Activity; Regulation; Regulatory Element; Relative (related person); Role; Series; Signal Pathway; Site; Specificity; Tail; Testing; Time; Tissues; Transcription Coactivator; Transcription Repressor/Corepressor; Transgenes; Up-Regulation; Valine; WNT Signaling Pathway; Work; Yeasts; Yolk Sac; base; brahma; cell type; chromatin remodeling; cofactor; interest; migration; mouse development; mutant; novel; polybromo; promoter; protein function; research study; transcription factor

The mammalian yolk sac provides an important nutritive role in the early postimplantatlon embryo. Yolk sac development is highly sensitive to the regulation of temporal and spatial expression of a number of genes; however, little work has been done on the relationship of chromatin structure and the transcriptional apparatus required specifically during morphogenesis of this tissue. Transcriptional activators bound to enhancers or promoters recruit chromatin·modifying complexes, which covalently modify N-terrninal histone tails or utilize ATPase activity to alter the conformation and/or position of nucleosomes. As a result, promoters adopt an ~open" chromatin configuration so transcription can be initiated. Conversely, transcriptional repressors ean recruit similar or identical complexes to other loci to establish a ·closedchromatin configuration that precludes transcription. Existing data suggest that these complexes regulate both the hematopoietic and non·hematopoietic aspects of yolk sac development but that these functions are independent of one another. To confirm this hypothesis, a 8rg1 cDNA-transgene will be specifically expressed In the hematopoietic compartment to rescue this defect. These data will confirm whether the complexes playa distinguishable role in endothelial cells of the yolk sac. In addition, based on preliminary data, experiments are proposed to test whether down regulation of Fz5 (frizzled 5) expression and upregulation of Cdh2 (eadherin 2) on the mutant background reduces the amount of free J)·catenin for WNT signaling and that this misregulation intersects with the Tgfb pathway. Misregulation of these pathways are known to regulate proliferation, migration, differentiation and apoptosis, all of which are key steps in yolk sac development.

哺乳动物卵黄囊在着床后早期胚胎发育中起重要的营养作用。卵黄囊的发展是高度敏感的时间和空间的表达调控的一些基因，然而，很少有工作已经做了染色质结构和转录装置的关系，特别是在此组织的形态发生。与增强子或启动子结合的转录激活剂募集染色质修饰复合物，其共价修饰N末端组蛋白尾部或利用ATP酶活性来改变核小体的构象和/或位置。因此，启动子采用"开放”染色质构型，因此可以启动转录。相反，转录抑制因子可以募集相似或相同的复合物到其他基因座，以建立一个封闭的染色质构型，从而阻止转录。现有的数据表明，这些复合物调节卵黄囊发育的造血和非造血方面，但这些功能是相互独立的。为了证实这一假设，8 rg 1 cDNA转基因将在造血区室中特异性表达以挽救这一缺陷。这些数据将证实复合物是否在卵黄囊的内皮细胞中发挥可区分的作用。此外，基于初步数据，提出实验以测试在突变体背景下Fz 5（卷曲5）表达的下调和Cdh 2（粘附素2）的上调是否减少用于WNT信号传导的游离β-连环蛋白的量，以及这种误调节与Tgfb途径交叉。已知这些通路的失调调节增殖、迁移、分化和凋亡，所有这些都是卵黄囊发育的关键步骤。