Control mechanisms of 5-hydroxymethylcytosine metabolism in human cells
人体细胞5-羟甲基胞嘧啶代谢的控制机制
基本信息
- 批准号:10629908
- 负责人:
- 金额:$ 13.8万
- 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:2023-09-01 至 2027-07-31
- 项目状态:未结题
- 来源:
- 关键词:AttentionBase Excision RepairsBiological AssayBiomedical ResearchBloodBrainCRISPR/Cas technologyCell LineCell physiologyCellsCpG dinucleotideCytosineDNADNA DamageDNA Double Strand BreakDNA MethylationDNA Modification MethylasesDNA RepairDNA biosynthesisDNA lesionDevelopmentDiseaseEnzymesEpigenetic ProcessFamilyFunctional disorderGene Expression RegulationGenerationsGenesGenetic TranscriptionGenomeGenome StabilityGlioblastomaGoalsHumanInduced pluripotent stem cell derived neuronsKnowledgeLightLinkLymphomaMalignant NeoplasmsMass Spectrum AnalysisMeasuresMediatingMetabolismMethylationMitoticModelingNeurodegenerative DisordersNeuronsNuclearNucleotidesOrganOrganismOutcomePathway interactionsPluripotent Stem CellsProcessProductionProteinsResistanceRoleSiteSurvival RateSystemTechniquesTestingThymine DNA GlycosylaseTimeTissue-Specific Gene ExpressionTissuesage relatedanti-cancer therapeuticcell typeconditional knockoutdemethylationdrug discoveryepigenetic markerepigenetic regulationhigh throughput screeninghuman DNAhuman diseaseknock-downmortalitynovelnovel markernovel therapeuticsoxidationpostmitoticrepairedresponsetranslocasetumor progression
项目摘要
Project Summary
The 5-hydroxymethylcytosine (5hmC) in mammalian DNA is drawing significant attention in epigenetics
because of its indispensable roles in gene expression regulation. The loss of 5hmCs in various cancers
including glioblastomas and lymphomas has been linked to the poor survival rate as well as the resistance to
anti-cancer therapeutics. Although there is amassing evidence of 5hmCs as a novel epigenetic marker, there is
very little understanding on how 5hmCs are enriched at specific loci in the genome. In this project, we aim to
identify the factors controlling the DNA demethylation pathway, which result in the formation of locus-specific
5hmCs in human neurons. For this purpose, proteins controlling the activity of ten-eleven translocase (TET)
family enzymes in the DNA demethylation pathway will be identified. To examine the function of candidate
proteins, we will take advantage of human induced-neurons (hiNs) derived from human induced-pluripotent
stem cells (hiPSCs). In addition, we will elucidate the role and fate of 5hmCs formed during DNA damage
repair process using blue light-inducible CRISPR/Cas9 technique. This robust experimental platform will
enable the rapid production of isogenic and homogenous neurons and other cell types. With this cell-based
assay system, high-throughput assays can be developed that will advance biomedical researches and drug
discoveries. Finally, we expect the successful completion of this project will expand our understanding on DNA
demethylation and their roles in epigenetics, development, and various human diseases.
项目概要
哺乳动物 DNA 中的 5-羟甲基胞嘧啶 (5hmC) 引起了表观遗传学的极大关注
因为它在基因表达调控中发挥着不可或缺的作用。各种癌症中 5hmC 的丢失
包括胶质母细胞瘤和淋巴瘤在内的癌症与低生存率以及耐药性有关
抗癌疗法。尽管有大量证据表明 5hmCs 作为一种新型表观遗传标记,但
对于 5hmC 如何在基因组中的特定位点富集,我们知之甚少。在这个项目中,我们的目标是
确定控制 DNA 去甲基化途径的因素,从而导致位点特异性的形成
人类神经元中的 5hmC。为此,控制十一十一转位酶 (TET) 活性的蛋白质
DNA 去甲基化途径中的家族酶将被鉴定。考察候选人的职能
蛋白质,我们将利用源自人类诱导多能神经元(hiN)的优势
干细胞(hiPSC)。此外,我们将阐明 DNA 损伤过程中形成的 5hmC 的作用和命运
使用蓝光诱导 CRISPR/Cas9 技术进行修复过程。这个强大的实验平台将
能够快速产生等基因和同质的神经元和其他细胞类型。有了这种基于细胞的
分析系统,可以开发高通量分析,这将促进生物医学研究和药物
发现。最后,我们期望这个项目的成功完成将扩大我们对DNA的理解
去甲基化及其在表观遗传学、发育和各种人类疾病中的作用。
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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