Connecting TCA cycle flux and epigenetic regulation of hematopoiesis
连接 TCA 循环通量和造血的表观遗传调控
基本信息
- 批准号:10397700
- 负责人:
- 金额:$ 2.89万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-05-01 至 2023-03-31
- 项目状态:已结题
- 来源:
- 关键词:ATP Citrate (pro-S)-LyaseAcetatesAcetyl Coenzyme AAcetylationAcetylesteraseAcute Myelocytic LeukemiaAffectBinding SitesBiological AssayBloodBone MarrowCRISPR screenCarbonCell Culture TechniquesCell LineageCellsCharacteristicsChromatinCitratesCitric Acid CycleConsensusDNADataDioxygenasesEnzymesEpigenetic ProcessEquilibriumErythroid CellsFlow CytometryFumaratesGene ExpressionGene Expression ProfileGenerationsGenesGenetic TranscriptionGlucoseGlutamatesGlutaminaseGlutamineHematologic NeoplasmsHematological DiseaseHematopoiesisHematopoieticHematopoietic stem cellsHistone AcetylationHistonesHomeostasisITGAM geneIn VitroLinkLymphoid CellMalignant NeoplasmsMeasuresMediatingMetabolicMetabolic PathwayMetabolismMethylationMethylcelluloseModificationMusMutationMyelogenousMyeloid CellsMyeloid Progenitor CellsNMR SpectroscopyOxaloacetatesOxidative PhosphorylationPlayPopulationProcessReactionRegulationRegulator GenesResearchRoleStimulusSuccinatesT cell differentiationTestingalpha ketoglutaratecellular developmentchemokinecomputerized toolsconditional knockoutcytokinedemethylationeffector T cellenzyme substrateepigenetic regulationexperimental studyextracellulargene regulatory networkhematopoietic differentiationhematopoietic stem cell differentiationhematopoietic stem cell fatehematopoietic stem cell self-renewalhistone acetyltransferasehistone methylationhistone modificationin vivoknockout animalmethylation patternmouse modelmultiple omicsnew therapeutic targetnovel therapeuticspreventprogramsreaction rateself-renewalsingle-cell RNA sequencingstem cell functionstem cell self renewalstem cellsstemnesstherapeutic targettranscription factortranscriptome
项目摘要
Summary
Hematopoietic Stem Cells (HSCs) possess distinct metabolic programs that regulate decisions to self-renew or
differentiate. Metabolic pathways are now recognized to modulate epigenetic marks through accessibility of
metabolic intermediates as substrates, including α-ketoglutarate (αKG) and acetyl-CoA for post-translational
demethylation or acetylation, respectively. Recent research suggests that perturbations of glutamine and
acetate metabolism may provoke lineage-specific differentiation by altering epigenetic-mediated chromatin
accessibility and gene expression responsible for lineage determination. Indeed, data from the Rathmell lab
demonstrates that disruption of Glutaminase (GLS), the entry point of glutamine into the metabolic pool
responsible for catalyzing glutamine to glutamate, changes histone methylation patterns to promote Th1 and
inhibit Th17 CD4+ effector T-cell differentiation, altering accessibility of the loci of cytokines Ifng and Il17. GLS
processes glutamine to replenish the carbon pool of the tricarboxylic acid (TCA) cycle, contributing to TCA cycle
intermediates that also regulate epigenetic modifying reactions. Specifically, αKG, succinate, and fumarate serve
as regulators and substrates of histone and DNA demethylation enzymes. Similarly, ATP citrate lyase (ACLY)
connects TCA cycle flux with the histone acetylation substrate pool by catalyzing cytosolic citrate into acetyl-
CoA. Maintaining both acetyl-CoA and αKG levels is crucial to epigenetic homeostasis, as reduced epigenetic
enzyme substrates and regulators have been shown to broadly limit epigenetic modifying reaction rates.
Preliminary data suggest that inhibiting ACLY promotes myeloid differentiation in cultured murine hematopoietic
stem cells (HSCs). Here, I propose to use conditional knockout animals previously analyzed for T cell
differentiation to disrupt GLS and ACLY in HSCs and LSCs and test the role of these enzymes in myeloid
differentiation. I hypothesize that disrupting ACLY and GLS will inhibit stem cell self-renewal while promoting
myelomonocytic differentiation. I will tackle this central hypothesis through two aims. Aim 1: Determine how
GLS or ACLY deficiency is sufficient to modulate HSC self-renewal and differentiation. This first aim
represents a functional characterization of HSC self-renewal and differentiation both in vitro and in vivo, utilizing
stem cell culture, flow cytometry, and CRISPR screen experiments. Aim 2: Establish how epigenetic
modification, gene regulator networks, and metabolic activity alter with GLS and ACLY deficiency in
HSCs. The second aim focuses on the mechanism behind changes in stem cell self-renewal and differentiation
examined in Aim 1. We will assess changes in chromatin accessibility, histone modifications, transcriptome
profiles, and metabolite concentrations to determine how GLS and ACLY deficiencies impact stem cell regulatory
networks. This project has the potential to uncover new interactions between epigenetics and metabolism in
normal hematopoiesis and acute myeloid leukemia with the prospect of identifying novel therapeutic targets for
hematologic malignancies.
总结
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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Dalton Lee Greenwood其他文献
Dalton Lee Greenwood的其他文献
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{{ truncateString('Dalton Lee Greenwood', 18)}}的其他基金
Connecting TCA cycle flux and epigenetic regulation of hematopoiesis
连接 TCA 循环通量和造血的表观遗传调控
- 批准号:
10383136 - 财政年份:2020
- 资助金额:
$ 2.89万 - 项目类别:
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