Genetic and Molecular Definition of Histone Modifying Enzyme Functions
Genetic and Molecular Definition of Histone Modifying Enzyme Functions
批准号:
10594451
负责人:
SHARON Y. R. DENT
金额:
$40.0万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-04-01 至 2024-03-31
关键词:
AddressAffectAllelesBiochemicalBiologicalBromodomainCell NucleusCellsCerebellar AtaxiaCerebellumChromatinComplexDevelopmentDiseaseEmbryoEnzymesFoundationsFundingGene ExpressionGene Expression RegulationGeneticGenetic TranscriptionGenomeGenomicsGoalsGrowthHistonesHumanKnowledgeLinkLoxP-flanked alleleMalignant NeoplasmsMammalian CellMolecularMutant Strains MiceMutateMutationNerve DegenerationNeurodegenerative DisordersPathway interactionsProteinsResearchRoleSAGASpinalTissuesVertebral columnWorkXCL1 genecell behaviorenzyme activityflexibilityhistone acetyltransferasehistone modificationhuman diseaseinsightnovelnovel therapeuticsprogramsstem cells
中文摘要
了解组蛋白修饰是如何调节组蛋白修饰的
了解正常人和正常人染色质组织和基因调控的机制
疾病状态。我们研究的总体目标是解决这个具有挑战性的问题,使用
基因和分子方法来定义哪些组蛋白修饰酶,并由此延伸,
组蛋白修饰,管理特定的基因表达程序,特别是生物
上下文。我们的工作主要集中在GCN5组蛋白乙酰转移酶(HAT)和
USP22组蛋白去泛素化酶(DUB),它们都是一个大的多蛋白的组成部分
集合被称为传奇。Gcn5,USP22和其他SAGA组件被牵连到
人类疾病,包括癌症和神经退行性变,但分子机制
潜在的这种影响尚不清楚。在过去的20年里,我们创造了一个新的工具包
Gcn5和Usp22突变小鼠和细胞,包括零等位基因、条件性(开花)等位基因和
点突变的等位基因(在Gcn5 HAT结构域、Gcn5溴结构域或USP22 Dub中
域),影响这些酶的活性。我们对Gcn5突变的研究揭示了关键
对这种HAT在发育过程中的转录和非转录功能的见解,
最近,他们揭示了Gcn5和Myc功能之间的重要联系
在正常的干细胞和癌症中。我们的USP22突变小鼠发现这个配对也很关键
对于胚胎存活,但通过不同的途径与那些受Gcn5丢失影响的。尽管
尽管取得了这些进展,但知识上的许多重大差距仍然存在。我们对……只有部分了解。
哪些转录程序需要哺乳动物细胞中的Gcn5。此外,现在已知Gcn5
是称为ATAC的第二组蛋白修饰复合体的一部分,但我们不知道Gcn5是如何
在这些复合体之间分配的或它们在发育或疾病中的相对作用。我们也
对USP22和SAGA配音模块在特定环境中的作用理解不全面
组织,如小脑,这是特别相关的,因为
佐贺配音模块与一种衰弱的神经退行性疾病脊髓小脑有关
共济失调7型(SCA7)。这个Mira将为我们提供稳定和灵活的资金,以继续我们的基因,
生物化学和分子研究来解决这些至关重要的问题。在更长的时间里
术语,GCN5和USP22正常功能的定义将为
为这些因子调节不当的疾病开发新的治疗方案。
英文摘要
Understanding how histone modifications are regulated is fundamentally important for
understanding mechanisms of chromatin organization and gene regulation in both normal and
disease states. The overall goal of our research is to address this challenging question, using
genetic and molecular approaches to define which histone modifying enzymes, and by extension,
which histone modifications, govern specific gene expression programs in particular biological
contexts. Our work is focused largely on the Gcn5 histone acetyltransferase (HAT) and the
USP22 histone deubiquitylase (DUB), which are both components of a large multiprotein
assembly termed SAGA. Gcn5, USP22 and other SAGA components have been implicated in
human maladies, including cancer and neurodegeneration, but the molecular mechanisms
underlying such effects are not known. Over the past 20 years, we have created a novel toolkit
of Gcn5 and USP22 mutant mice and cells, including null alleles, conditional (floxed) alleles, and
point mutated alleles (in the Gcn5 HAT domain, the Gcn5 bromodomain, or the USP22 DUB
domain) that affect the activity of these enzymes. Our studies of Gcn5 mutations revealed key
insights to both transcriptional and non-transcriptional functions for this HAT during development,
and most recently, they revealed important connections between Gcn5 and Myc functions both in
normal stem cells and in cancer. Our USP22 mutant mice revealed that this DUB is also critical
for embryo survival, but through different pathways than those affected by Gcn5 loss. Despite
these advances, many significant gaps in knowledge still remain. We have only a partial view of
which transcription programs require Gcn5 in mammalian cells. Moreover, Gcn5 is now known
to be part of a second histone modifying complex called ATAC, but we do not know how Gcn5 is
apportioned between these complexes or their relative roles in development or disease. We also
have an incomplete understanding of the roles of USP22 and the SAGA DUB module in specific
tissues such as the cerebellum, which is especially relevant since specific components of the
SAGA DUB module are linked to a debilitating neurodegenerative disease, spinal cerebellar
ataxia type 7 (SCA7). This MIRA will provide us stable and flexible funding to continue our genetic,
biochemical, and molecular studies to address these critically important questions. In the longer
term, definition of the normal functions of Gcn5 and USP22 will provide molecular foundations for
development of new therapeutic options for diseases in which these factors are mis-regulated.
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会议论文
Genetic and Molecular Definition of Histone Modifying Enzyme Functions
-
批准号:10364649
-
项目类别:
-
资助金额:$40.0万
-
财政年份:2019
-
负责人:SHARON Y. R. DENT
-
依托单位:
Genetic and Molecular Definition of Histone Modifying Enzyme Functions
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批准号:9889968
-
项目类别:
-
资助金额:$40.0万
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财政年份:2019
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负责人:SHARON Y. R. DENT
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依托单位:
Defining USP22 Functions During Mammalian Development
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批准号:8825514
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项目类别:
-
资助金额:$31.64万
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财政年份:2012
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负责人:SHARON Y. R. DENT
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依托单位:
Defining USP22 Functions During Mammalian Development
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批准号:10197175
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项目类别:
-
资助金额:$39.96万
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财政年份:2012
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负责人:SHARON Y. R. DENT
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依托单位:
Defining USP22 Functions During Mammalian Development
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批准号:8448604
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项目类别:
-
资助金额:$32.18万
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财政年份:2012
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负责人:SHARON Y. R. DENT
-
依托单位:
Defining USP22 Functions During Mammalian Development
-
批准号:9769094
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项目类别:
-
资助金额:$40.78万
-
财政年份:2012
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负责人:SHARON Y. R. DENT
-
依托单位:
Defining USP22 Functions During Mammalian Development
-
批准号:8633047
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项目类别:
-
资助金额:$32.69万
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财政年份:2012
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负责人:SHARON Y. R. DENT
-
依托单位:
Defining USP22 Functions During Mammalian Development
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批准号:8235526
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项目类别:
-
资助金额:$35.43万
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财政年份:2012
-
负责人:SHARON Y. R. DENT
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依托单位:
Functions of Mammalian Histone Modifiers
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批准号:7904468
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项目类别:
-
资助金额:$11.55万
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财政年份:2009
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负责人:SHARON Y. R. DENT
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依托单位:
Functions of Mammalian Histone Modifiers
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批准号:6739081
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项目类别:
-
资助金额:$26.43万
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财政年份:2003
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负责人:SHARON Y. R. DENT
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依托单位:
Functions of Mammalian Histone Modifiers
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批准号:7037639
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项目类别:
-
资助金额:$25.8万
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财政年份:2003
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负责人:SHARON Y. R. DENT
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依托单位:
Functions of Mammalian Histone Modifiers
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批准号:6594658
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项目类别:
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资助金额:$29.18万
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财政年份:2003
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负责人:SHARON Y. R. DENT
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依托单位:
Functions of Mammalian Histone Modifiers
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批准号:8879661
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项目类别:
-
资助金额:$32.3万
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财政年份:2003
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负责人:SHARON Y. R. DENT
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依托单位:
Functions of Mammalian Histone Modifiers
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批准号:8085820
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项目类别:
-
资助金额:$30.19万
-
财政年份:2003
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负责人:SHARON Y. R. DENT
-
依托单位:
Functions of Mammalian Histone Modifiers
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批准号:7645688
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项目类别:
-
资助金额:$30.8万
-
财政年份:2003
-
负责人:SHARON Y. R. DENT
-
依托单位:
Functions of Mammalian Histone Modifiers
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批准号:7530380
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项目类别:
-
资助金额:$30.8万
-
财政年份:2003
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负责人:SHARON Y. R. DENT
-
依托单位:
Functions of Mammalian Histone Modifiers
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批准号:6882636
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项目类别:
-
资助金额:$26.43万
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财政年份:2003
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负责人:SHARON Y. R. DENT
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依托单位:
Functions of Mammalian Histone Modifiers
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批准号:9251293
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项目类别:
-
资助金额:$32.3万
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财政年份:2003
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负责人:SHARON Y. R. DENT
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依托单位:
Organization of Chromatin by Global Regulators in Yeast
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批准号:6965140
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项目类别:
-
资助金额:$28.88万
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财政年份:1994
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负责人:SHARON Y. R. DENT
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依托单位:
Organization of Chromatin by Global Regulators in Yeast
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批准号:7432506
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项目类别:
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资助金额:$27.38万
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财政年份:1994
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负责人:SHARON Y. R. DENT
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依托单位:
海外基金