Ikaros regulation: Study on hemolymphopoiesis
Ikaros 调节:血淋巴细胞生成的研究
基本信息
- 批准号:10437875
- 负责人:
- 金额:$ 75.47万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:3-DimensionalAddressAntibody FormationArchitectureB cell differentiationB cell repertoireB-Cell Acute Lymphoblastic LeukemiaB-LymphocytesBehaviorBinding ProteinsBinding SitesBiochemicalBioinformaticsCell NucleusCellsChromatinChromatin StructureComplexConfined SpacesCoupledDNADNA cassetteDataDevelopmentDimerizationDiseaseEngineeringEnhancersEpithelialEpithelial CellsEventGene ExpressionGenesGenetic TranscriptionGenomeGoalsHigher Order Chromatin StructureHistonesIgKIkaros proteinKnowledgeLymphoidMalignant - descriptorMediatingModelingMusMutationNeuronsNuRD complexNuclearOrganization administrative structuresPathogenesisPatientsPhaseProcessPropertyProteinsRegulationRepressionResistanceRoleSamplingSiteStructureSystemTertiary Protein StructureTestingTissue DifferentiationTissuesWorkbasecell typechromatin modificationcohesincomparativeexperimental studyfightinggain of functionhigh riskhistone modificationin vitro Assayin vivoloss of functionmutantnovelnovel strategiespromoterrelating to nervous systemsegregationtool
项目摘要
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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KATIA GEORGOPOULOS其他文献
KATIA GEORGOPOULOS的其他文献
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{{ truncateString('KATIA GEORGOPOULOS', 18)}}的其他基金
Epigenetic regulation of epidermal proinflammatory responses
表皮促炎症反应的表观遗传调控
- 批准号:
10931159 - 财政年份:2023
- 资助金额:
$ 75.47万 - 项目类别:
Epigenetic regulation of proinflammatory responses in the skin
皮肤促炎症反应的表观遗传调控
- 批准号:
9313788 - 财政年份:2016
- 资助金额:
$ 75.47万 - 项目类别:
Epigenetic regulation of proinflammatory responses in the skin
皮肤促炎症反应的表观遗传调控
- 批准号:
9177449 - 财政年份:2016
- 资助金额:
$ 75.47万 - 项目类别:
Role of IKAROS in the Biology and Therapy of High-Risk Precursor B-Cell Leukemia
IKAROS 在高危前体 B 细胞白血病的生物学和治疗中的作用
- 批准号:
8974821 - 财政年份:2014
- 资助金额:
$ 75.47万 - 项目类别:
Role of IKAROS in the Biology and Therapy of High-Risk Precursor B-Cell Leukemia
IKAROS 在高危前体 B 细胞白血病的生物学和治疗中的作用
- 批准号:
8802836 - 财政年份:2014
- 资助金额:
$ 75.47万 - 项目类别:
Ikaros regulation: study on hemo-lymphopoiesis
Ikaros 调节:造血淋巴细胞的研究
- 批准号:
8882314 - 财政年份:2011
- 资助金额:
$ 75.47万 - 项目类别:
Ikaros-based epigenetic regulation of T cell leukemogenesis
基于 Ikaros 的 T 细胞白血病发生的表观遗传调控
- 批准号:
8464910 - 财政年份:2011
- 资助金额:
$ 75.47万 - 项目类别:
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