Scalable platforms for understudied histone modifications and modifiers
用于未充分研究的组蛋白修饰和修饰剂的可扩展平台
基本信息
- 批准号:10567849
- 负责人:
- 金额:$ 32.58万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-06 至 2027-06-30
- 项目状态:未结题
- 来源:
- 关键词:AcetylationAddressAdoptedAffinityAmino AcidsAntibodiesArginineBindingBinding ProteinsBiochemicalBiochemistryBiologicalBiological AssayBiological ProcessBiologyBiosensorBypassCell physiologyChIP-seqChemicalsChromatinChromatin StructureComplementComplexCost Effectiveness AnalysisDNADNA BindingDNA Modification ProcessDiseaseDopamineEngineeringEnzymesEpigenetic ProcessEukaryotaGene ExpressionGene Expression RegulationGene SilencingGenerationsGenetic TranscriptionGenomeGenomic DNAGlutamineGoalsHealthHeartHeritabilityHistone CodeHistonesHumanLysineMeasurementMediatingMethylationModificationNeurotransmittersPatternPlayPost-Translational Protein ProcessingProtein EngineeringProteinsQuality ControlRNAReaderReagentRecombinant ProteinsRegulationResearchResearch PersonnelRoleSerotoninSet proteinSiteSpecificityStructureSurfaceSystemTranscriptional RegulationWorkWritingYeastsacyl groupbiochemical toolscell behaviorcell growth regulationcombinatorialcost efficientepigenetic silencinggene repressiongenome-widehistone acetyltransferasehistone modificationhistone-binding proteinslive cell imagingmonoaminenext generationopen sourcepreferencetoolvirtual
项目摘要
PROJECT SUMMARY/ABSTRACT
Eukaryotic genomic DNA is extensively associated with proteins and RNAs to form chromatin. Through its control
of gene expression, changes in chromatin biochemistry and structure underlie nearly all cellular processes.
Post-translational modifications of histone proteins that bind genomic DNA play an especially critical role in
regulating chromatin structure and function. Modifications of certain histone residues influence the binding of
histone proteins to DNA as well as the interactions of other proteins that specifically recognize these
modifications. The specific pattern of histone modifications acts as a “histone code” to determine the set of
proteins that interact with histones and histone-bound DNA, and consequently participate in diverse cellular
processes. Therefore, identification of specific histone modifications, quantitative assessment of the interactions
they mediate, and characterization of enzymes that modify histones is essential for understanding chromatin
regulation of complex cellular behavior. However, unraveling the histone code is a daunting challenge due to its
complexity – over eighty different amino acid residues on five histone proteins undergo over twenty distinct
known post-translational modifications. Despite significant advances in research on some histone modifications
such as acetylation and methylation, the vast majority of histone modifications remains understudied. Further, a
vast majority of enzymes that write even extensively researched modifications like acetylation remain
understudied. We propose to address the critical gap in essential biochemical tools and accessible experimental
platforms that has hindered research on understudied histone modifications and modifiers. Specifically, we will
harness next generation yeast surface display systems as scalable platforms for high throughput studies on
understudied histone modifications and modifiers, as well as platforms for engineering biochemical reagents for
chromatin research. In addition to understudied histone acetyltransferases, we will focus on three classes of
histone modifications: (i) citrullination of arginine (ii) acyl modification of lysine by non-acetyl groups
(propionylation, butyrylation, crotonylation), and (iii) monoamine modification of glutamine by serotonin and
dopamine. In Aim 1, we will develop a platform for efficient generation of affinity reagents with high specificity
that can serve as genetically encoded biosensors for live cell imaging, as well as in conventional analyses like
ChIP-seq and CUT&Tag. In Aim 2, we will develop a platform for high throughput identification and quantification
of binding interactions mediated by histone modifications. In Aim 3, we will develop a platform for high throughput
interrogation of residue preferences of writers. Our work will develop “open source” platforms that are scalable,
cost-efficient, and easily adopted by other investigators in chromatin biology. Such platforms will serve as strong
complements to traditional biochemical assays by enabling research on both common and understudied histone
modifications, and unlocking new high throughput measurements and research questions in chromatin biology.
项目总结/文摘
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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Albert Keung其他文献
Albert Keung的其他文献
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{{ truncateString('Albert Keung', 18)}}的其他基金
Engineering locus-specific binders to DNA modifications
工程化位点特异性结合剂以进行 DNA 修饰
- 批准号:
10593668 - 财政年份:2023
- 资助金额:
$ 32.58万 - 项目类别:
Intracellular CRISPR gRNA assembly for massively multiplexed, one pot, (epi)genetic screening
用于大规模多重、一锅、(表观)遗传筛选的细胞内 CRISPR gRNA 组装
- 批准号:
9795162 - 财政年份:2019
- 资助金额:
$ 32.58万 - 项目类别:
Intracellular CRISPR gRNA assembly for massively multiplexed, one pot, (epi)genetic screening
用于大规模多重、一锅、(表观)遗传筛选的细胞内 CRISPR gRNA 组装
- 批准号:
10242748 - 财政年份:2019
- 资助金额:
$ 32.58万 - 项目类别:
The Epigenome in Substance Abuse Disorders: Engineering New Tools to Dissect Function from Form
药物滥用疾病中的表观基因组:设计新工具从形式中剖析功能
- 批准号:
9376441 - 财政年份:2017
- 资助金额:
$ 32.58万 - 项目类别:
The Epigenome in Substance Abuse Disorders: Engineering New Tools to Dissect Function from Form
药物滥用疾病中的表观基因组:设计新工具从形式中剖析功能
- 批准号:
10250507 - 财政年份:2017
- 资助金额:
$ 32.58万 - 项目类别:
The Epigenome in Substance Abuse Disorders: Engineering New Tools to Dissect Function from Form
药物滥用疾病中的表观基因组:设计新工具从形式中剖析功能
- 批准号:
9761510 - 财政年份:2017
- 资助金额:
$ 32.58万 - 项目类别:
Genetically encoded live cell sensors of chromatin state
染色质状态的基因编码活细胞传感器
- 批准号:
9357582 - 财政年份:2016
- 资助金额:
$ 32.58万 - 项目类别:
Genetically encoded live cell sensors of chromatin state
染色质状态的基因编码活细胞传感器
- 批准号:
9225678 - 财政年份:2016
- 资助金额:
$ 32.58万 - 项目类别:
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