Ikaros regulation: Study on hemolymphopoiesis

Ikaros 调节：血淋巴细胞生成的研究

• 批准号: 10437875
• 负责人: KATIA GEORGOPOULOS
• 金额: $ 75.47万
• 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/10437875
• 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 我们建议通过研究以下因素的作用来阐明3D基因组组织的谱系特异性机制： IKAROS：a）基于增强子的长距离相互作用支持的调控环（RL）形成，和B） 结构环（SL）和绝缘结构域的形成支持CTCF相互作用在建筑网站。 目标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强化学习和一类新的动态增强子之间的功能相互作用。 我们提出的结构环（DSL）是谱系隔离不可或缺的。他们在血统隔离中的作用是 通过比较分析IKAROS功能丧失后它们的形成进行测试， 在上皮细胞中起作用。我们检验了IKAROS抑制这些DSL的假设，这些DSL的诱导导致 超谱系基因谱的去抑制，特别是那些适合于上皮细胞的基因谱。我们研究是否 这是IKAROS和CD3D复合物共同占据CTCF位点子集的直接机制， 当任何一个因素被移除时，形成DSL。或者，我们测试IKAROS是否抑制DSL是间接的， 并与IKAROS作为RL组织者的角色有关。 目标2。IKAROS调控超级增强子组装的机制 在这里，我们专注于IKAROS介导组装的超级增强子（SE）的机制。我们 假设IKAROS蛋白在不同染色体位点结合之间的高级相互作用 有助于SE结构的形成，该结构将调控位点和相关因子截留在封闭的 空间来调节其功能。不同IKBS的作用和对特定IKAROS蛋白的需求 测试组件SE中的域。我们研究了组装IKAROS复合物在分离 将染色质结合到细胞核中具有独特性质的区域。最后，我们测试了 IKAROS在调节SE组装中涉及Igk位点收缩。