The role of ALKBH5-mediated RNA demethylation in the maintenance of genomic stability in HSPCs
ALKBH5 介导的 RNA 去甲基化在维持 HSPC 基因组稳定性中的作用
基本信息
- 批准号:10445661
- 负责人:
- 金额:$ 47.85万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-01 至 2026-05-31
- 项目状态:未结题
- 来源:
- 关键词:AgingApoptosisBiological ProcessCD34 geneCell DeathCell MaintenanceCellsChromatinDNA DamageDNA RepairDNA lesionDevelopmentDysmyelopoietic SyndromesFunctional disorderGene ExpressionGene Expression RegulationGenetic TranscriptionGenome StabilityGenomic InstabilityGoalsGrowthHematological DiseaseHematopoieticHematopoietic stem cellsHistone DeacetylaseHumanHuman Cell LineIn VitroLifeLong-Term EffectsMaintenanceMalignant - descriptorMalignant NeoplasmsMediatingMediator of activation proteinMessenger RNAMethylationModelingModificationMolecularMusMutagenesisOncogene ActivationOncogenesOxidative StressPathway interactionsPatientsPhenocopyPhysiologicalPlayPolyribosomesPost-Transcriptional RegulationPost-Translational Protein ProcessingProcessRNARNA methylationReactive Oxygen SpeciesRoleSourceSpeedStem Cell DevelopmentStressSystemTestingTimeTransgenic MiceTransgenic OrganismsUp-RegulationXenograft procedurecell injurycrosslinking and immunoprecipitation sequencingdemethylationepigenetic regulationgenome integrityhematopoietic stem cell self-renewalin vivoinsightknock-downleukemic transformationnovelnovel therapeutic interventionoverexpressionpreventrepairedresponseribosome profilingself-renewalstem cell functionstem cellstranscriptome sequencingtumorigenesis
项目摘要
Abstract
Myelodysplastic syndromes (MDS) are a group of diverse malignant hematological disorders that
originate from hematopoietic stem cells (HSCs). Increased levels of reactive oxygen species (ROS) and DNA
damage are commonly detected in hematopoietic cells from MDS patients. An elevated level of ROS,
generated from either endogenous or exogenous sources including oncogene activation, leads to loss of
quiescence and self-renewal of HSCs. ROS-induced DNA damage speeds up the aging process of stem cells
and contributes to the mutagenesis associated with cancer development. m6A RNA methylation plays a
significant role in multiple biological processes by introducing another layer of post-transcriptional regulation of
gene expression within cells. The goal of this project is to elucidate the significant role of ALKBH5-mediated
epigenetic regulation in the maintenance of genomic stability in hematopoietic stem/progenitor cell (HSPCs)
during oxidative stress, and how deregulation of ALKBH5 contributes to promotion of leukemic transformation
of HSPCs in the initiation and development of MDS. We found that ROS significantly increased global m6A
RNA methylation in human cell lines, and that the elevation of m6A mRNA methylation is required for rapidly
repairing ROS-induced DNA lesions and preventing cell death. Interestingly, we found that ALKBH5, the m6A
RNA demethylase, is responsible for ROS-induced elevation of m6A mRNA methylation. ROS induced post-
translational modification of ALKBH5, and inhibited the demethylase activity of ALKBH5. We showed that
forced expression of ALKBH5 inhibited ROS-induced m6A mRNA methylation and significantly delayed repair
of ROS-induced DNA damage. Thus, we hypothesize that aberrant expression of ALKBH5 disrupts HSPC
functions by negatively influencing genome integrity and survival of HSPCs, thereby contributing to leukemic
transformation of HSPCs during the initiation and development of MDS. In this proposal, we will determine 1)
the role and underlying mechanism of ALKBH5 in the maintenance of genomic stability in HSPCs in response
to oxidative stress; 2) the effects of ALKBH5/Alkbh5 overexpression on the maintenance of mouse and human
primary HSPCs during ROS stress in vivo; and 3) whether ALKBH5/Alkbh5 is required for the maintenance of
pre-leukemic stem cells (pre-LSCs) in MDS. Our study will provide new insights into novel mechanisms of
MDS development and epitranscriptional regulation of gene expression in HSPCs in response to oxidative
stress. Additionally, our study will provide the first set of evidence to support a significant role of ALKBH5-
mediated m6A mRNA demethylation in the maintenance of normal HSPCs and pre-leukemic stem cell (pre-
LSCs).
摘要
项目成果
期刊论文数量(0)
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会议论文数量(0)
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Zhijian Qian其他文献
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{{ truncateString('Zhijian Qian', 18)}}的其他基金
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RBM33 在白血病发生中的新作用和机制
- 批准号:
10343898 - 财政年份:2022
- 资助金额:
$ 47.85万 - 项目类别:
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$ 47.85万 - 项目类别:
The role of ALKBH5-mediated RNA demethylation in the maintenance of genomic stability in HSPCs
ALKBH5 介导的 RNA 去甲基化在维持 HSPC 基因组稳定性中的作用
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The role of ALKBH5-mediated RNA demethylation in the maintenance of genomic stability in HSPCs
ALKBH5 介导的 RNA 去甲基化在维持 HSPC 基因组稳定性中的作用
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