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.
项目摘要
哺乳动物DNA中的5-羟甲基胞嘧啶(5hmC)在表观遗传学中引起了广泛的关注
因为它在基因表达调控中起着不可或缺的作用。多种癌症中5HMC的丢失
包括胶质母细胞瘤和淋巴瘤与低存活率和抗药性有关。
抗癌疗法。尽管有越来越多的证据表明5hmcs是一种新的表观遗传标记,但有
对5HMC是如何在基因组中的特定位点上富集的知之甚少。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,这些因素导致形成位点特异性
5HMC在人脑神经元中的表达。为此,控制十-十一转位酶(Tet)活性的蛋白质
DNA去甲基化途径中的家族酶将被确定。考查考生的作用
蛋白质,我们将利用来自人类诱导多能性的人类诱导神经元(HINS)
干细胞(HiPSCs)。此外,我们还将阐明在dna损伤过程中形成的5hmcs的作用和命运。
修复工艺采用蓝光诱导CRISPR/CAS9技术。这一强大的实验平台将
使同基因和同源神经元及其他类型的细胞能够快速产生。使用这种基于细胞的
测试系统,可以开发高通量测试,这将促进生物医学研究和药物
发现。最后,我们期待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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