Ikaros regulation: Study on hemolymphopoiesis

Ikaros 调节：血淋巴细胞生成的研究

• 批准号: 10299175
• 负责人: KATIA GEORGOPOULOS
• 金额: $ 75.14万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-05 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10299175
• 关键词: 3-Dimensional; Address; Antibody Formation; Architecture; B cell differentiation; B cell repertoire; B-Cell Acute Lymphoblastic Leukemia; B-Lymphocytes; Behavior; Binding Proteins; Binding Sites; Biochemical; Bioinformatics; Cell Nucleus; Cells; Chromatin; Chromatin Structure; Complex; Confined Spaces; Coupled; DNA; DNA cassette; Data; Development; Dimerization; Disease; Engineering; Enhancers; Epithelial; Epithelial Cells; Event; Gene Expression; Genes; Genetic Transcription; Genome; Goals; Higher Order Chromatin Structure; Histones; IgK; Ikaros protein; Knowledge; Lymphoid; Malignant - descriptor; Mediating; Modeling; Mus; Mutation; Neurons; NuRD complex; Nuclear; Organization administrative structures; Pathogenesis; Patients; Phase; Process; Property; Proteins; Regulation; Repression; Resistance; Role; Sampling; Site; Structure; System; Tertiary Protein Structure; Testing; Tissue Differentiation; Tissues; Work; base; cell type; chromatin modification; cohesin; comparative; experimental study; fighting; gain of function; high risk; histone modification; in vitro Assay; in vivo; loss of function; mutant; novel; novel strategies; promoter; relating to nervous system; segregation; tool

ABSTRACT We propose to elucidate the lineage-specific mechanisms of 3D genome organization by studying the role of IKAROS in: a) regulatory loop (RL) formation supported by enhancer-based long-distance interactions and b) structural loop (SL) and insulated domain formation supported by CTCF interactions at architectural sites. Aim1. Lineage-specific regulation of genome organization principles. Here we address the functional interactions between enhancer-based RL and a novel class of dynamic structural loops (DSL) that we propose are integral to lineage segregation. Their role in lineage segregation is tested by comparative analysis of their formation after IKAROS-loss-of-function in large preB and -gain-of- function in epithelial cells. We test the hypothesis that IKAROS represses these DSL whose induction causes de-repression of extra-lineage gene profiles, notably those appropriate for epithelial cells. We examine whether this is a direct mechanism by which IKAROS and the NURD complex co-occupy a subset of CTCF sites that form DSL when either factors are removed. Alternatively we test whether IKAROS repression of DSL is indirect and relates to IKAROS’ role as an RL organizer. Aim2. Mechanisms of IKAROS regulation of super-enhancer assemblies Here we focus on the mechanisms by which IKAROS mediates assembly of super-enhancers (SE). We hypothesize that higher order interactions between IKAROS proteins bound at different chromosomal sites contributes to the formation of SE structures that entrap regulatory sites and associated factors in a confined space to mediate their function. The role of distinct IKBS and the requirement for specific IKAROS protein domains in the assembly SE is tested. We examine the role of assembled IKAROS complexes in segregating bound chromatin into regions of the nucleus with distinctive properties. Finally, we test whether the role of IKAROS in regulating SE assemblies is involved in Igk locus contraction.

摘要 我们建议通过研究3D基因组组织的作用来阐明谱系特有的机制 伊卡洛斯在：a)由基于增强子的远程相互作用支持的调控环(RL)的形成和b) 建筑现场CTCF相互作用支持的结构环(SL)和绝缘域的形成。 目的：1.基因组组织原则的谱系特异性调节。 在这里，我们解决了基于增强子的RL和一类新的动态RL之间的功能相互作用 我们提出的结构环(DSL)是血统分离不可或缺的部分。他们在世系隔离中的作用是 通过比较分析IKAROS在大PREB中的功能损失和增益后它们的形成 在上皮细胞中发挥作用。我们测试了IKAROS抑制这些DSL的假设，这些DSL的诱导导致 去抑制系外基因图谱，特别是那些适合于上皮细胞的基因图谱。我们研究是否 这是一种直接机制，通过这种机制，IKAROS和NuRD建筑群共同占据了CTCF站点的子集， 删除任一因素后形成DSL。或者，我们测试IKAROS对DSL的抑制是否是间接的 并涉及IKAROS作为RL组织者的角色。 AIM2.IKAROS对超级增强子组件的调控机制 在这里，我们重点介绍IKAROS介导超级增强子(SE)组装的机制。我们 假设结合在不同染色体位置的IKAROS蛋白之间的高阶相互作用 有助于形成SE结构，该结构将调控位点和相关因素困在受限的 空间来调停他们的功能。不同的IKBS的作用及其对特定IKAROS蛋白的需求 测试组件SE中的域。我们研究了组装的IKAROS复合体在分离中的作用 将染色质结合到具有不同性质的核区域。最后，我们检验了这一角色 调节SE组装的Ikaros参与了Igk基因位点的收缩。