LINE-1 Retrotransposition in Human Embryonic Stem Cells
人类胚胎干细胞中的 LINE-1 逆转座
基本信息
- 批准号:7858199
- 负责人:
- 金额:$ 23.8万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-08-01 至 2012-05-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAlu ElementsAreaAtlasesBar CodesBiological AssayBiological ModelsCell Culture TechniquesCell LineCellsChromosomesColon CarcinomaCultured CellsDNA SequenceDevelopmentDiseaseEmbryoEmbryonic DevelopmentEngineeringEventEvolutionFunctional RNAGenesGenomeGenomic InstabilityGerm LinesHemophilia AHereditary DiseaseHumanHuman DevelopmentHuman EngineeringHuman GenomeIn VitroL1 ElementsLaboratoriesLibrariesLong Interspersed ElementsMediatingMichiganMolecularMonitorMuscular DystrophiesMutateMutation SpectraNeuronal DifferentiationParentsPatternPlayProcessProteinsProtocols documentationPseudogenesRattusRetrotranspositionRetrotransposonRoleShort Interspersed Nucleotide ElementsSomatic CellStagingSystemTestingTransgenic MiceUniversitiesVariantbasecell typehuman DNAhuman embryonic stem cellin vitro Modelin vivonerve stem cellrelating to nervous systemtumorigenesis
项目摘要
DESCRIPTION (provided by applicant): Long Interspersed Element-1 (LINE-1 or L1) is an abundant retrotransposon that comprises ~17% of human DNA. The overwhelming majority of L1s can no longer move (i.e., retrotranspose). However, the average human genome contains ~80-100 retrotransposition-competent L1s (RC-L1s) and their mobility, in both germ line and somatic cells, has resulted in a variety of genetic disorders, including Hemophilia A, muscular dystrophy, and colon cancer. The proteins encoded by RC-L1s also likely are responsible for the mobilization of Alu elements, certain Short Interspersed Elements (SINEs) and the formation of processed pseudogenes, which together comprise ~13% of human DNA. Thus, either directly or by the promiscuous mobilization of cellular RNAs, L1-mediated retrotransposition events are responsible for at least one billion bases in human DNA and have had a tremendous impact on human genome evolution. Recent studies indicate that L1 retrotransposition events can occur during early embryogenesis and in neural progenitor cells. We hypothesize that hES cells represent a developmentally relevant in vitro model system to study the mechanisms by which L1- mediated retrotransposition events impact genome integrity at various stages of human development. An understanding of the basic molecular processes that impact genome integrity in hES cells is important to evaluate since these cells ultimately may be used therapeutically to treat a wide-range of diseases. The specific aims of this proposal are: 1. To determine the impact of L1 retrotransposition events in hES cells. 2. To determine the constellation of endogenous L1s that are mobilized in hES cells. 3. To determine how L1 retrotransposition impacts neuronal differentiation.
Lay Narrative: LINE-1 elements are DNA sequences that can "jump" from one area of a chromosome into another by a process called retrotransposition. They comprise ~17% of the human DNA and have played a major role in genome evolution. The vast majorities of LINE-1 elements are mutated and can no longer jump; however, ~100 LINE-1 elements are still able to mobilize. Deleterious LINE-1 insertions into genes have caused diseases such as Hemophilia A, muscular dystrophy, and also are implicated in tumorigenesis. The proteins encoded by LINE-1 elements also are responsible for the mobilization of Alu elements, certain Short Interspersed Elements (SINEs) and the formation of processed pseudogenes, which together comprise at least 13% of human DNA. Thus, either directly or by the promiscuous mobilization of cellular RNAs, L1-mediated retrotransposition events are responsible for at least one billion bases in human DNA and have had a tremendous impact on human genome evolution. Despite these findings, it still is unclear how often, in what cell types, and when during development L1 retrotransposes in vivo. Recent studies indicate that L1 retrotransposition events can occur during early embryogenesis and in neural progenitor cells. We hypothesize that hES cells represent a developmentally relevant in vitro model system to study the mechanisms by which L1-mediated retrotransposition events impact genome integrity at various stages of human development. An understanding of the basic molecular processes that impact genome integrity in hES cells is important to evaluate since these cells ultimately may be used therapeutically to treat a wide-range of diseases.
描述(由申请人提供):长散布元件-1(LINE-1或L1)是一种丰富的反转录转座子,占人类DNA的约17%。绝大多数的L1不再能够移动(即,逆转置)。然而,平均人类基因组包含约80-100个具有逆转录转座能力的L1(RC-L1),它们在生殖系和体细胞中的移动性导致了各种遗传疾病,包括血友病A,肌肉萎缩症和结肠癌。由RC-L1编码的蛋白质也可能负责Alu元件、某些短散布元件(西内斯)的移动和加工假基因的形成,它们共同构成约13%的人类DNA。因此,无论是直接还是通过细胞RNA的混杂动员,L1介导的逆转录转座事件负责人类DNA中至少10亿个碱基,并对人类基因组进化产生了巨大的影响。最近的研究表明,L1反转录转座事件可以发生在早期胚胎发育和神经祖细胞。我们假设hES细胞代表了一个发育相关的体外模型系统,以研究L1介导的逆转录转座事件在人类发育的各个阶段影响基因组完整性的机制。对影响hES细胞基因组完整性的基本分子过程的理解对于评估是重要的,因为这些细胞最终可用于治疗广泛的疾病。该提案的具体目标是:1.确定hES细胞中L1逆转录转座事件的影响。2.确定hES细胞中动员的内源性L1的星座。3.确定L1反转录转座如何影响神经元分化。
LINE-1元件是DNA序列,可以通过一种称为反转录转座的过程从染色体的一个区域“跳跃”到另一个区域。它们占人类DNA的约17%,在基因组进化中发挥了重要作用。绝大多数LINE-1元件都发生了突变,不能再跳跃;然而,大约100个LINE-1元件仍然能够动员。将LINE-1插入到基因中会导致血友病A、肌营养不良等疾病,并且还与肿瘤发生有关。由LINE-1元件编码的蛋白质还负责Alu元件、某些短散布元件(西内斯)的移动和加工假基因的形成,它们一起构成至少13%的人DNA。因此,无论是直接还是通过细胞RNA的混杂动员,L1介导的逆转录转座事件负责人类DNA中至少10亿个碱基,并对人类基因组进化产生了巨大的影响。尽管有这些发现,但仍不清楚L1在体内逆转录转座的频率、细胞类型以及发育过程中的时间。最近的研究表明,L1反转录转座事件可以发生在早期胚胎发育和神经祖细胞。我们假设hES细胞代表了一个发育相关的体外模型系统,以研究L1介导的逆转录转座事件在人类发育的各个阶段影响基因组完整性的机制。对影响hES细胞基因组完整性的基本分子过程的理解对于评估是重要的,因为这些细胞最终可用于治疗广泛的疾病。
项目成果
期刊论文数量(0)
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JOHN V. MORAN其他文献
JOHN V. MORAN的其他文献
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{{ truncateString('JOHN V. MORAN', 18)}}的其他基金
2/3 Schizophrenia Genetics and Brain Somatic Mosaicism
2/3 精神分裂症遗传学和脑体细胞镶嵌
- 批准号:
9251022 - 财政年份:2016
- 资助金额:
$ 23.8万 - 项目类别:
2/3 Schizophrenia Genetics and Brain Somatic Mosaicism
2/3 精神分裂症遗传学和脑体细胞镶嵌
- 批准号:
8878527 - 财政年份:2015
- 资助金额:
$ 23.8万 - 项目类别:
2/3 Schizophrenia Genetics and Brain Somatic Mosaicism
2/3 精神分裂症遗传学和脑体细胞镶嵌
- 批准号:
9902954 - 财政年份:2015
- 资助金额:
$ 23.8万 - 项目类别:
2/3 Schizophrenia Genetics and Brain Somatic Mosaicism
2/3 精神分裂症遗传学和脑体细胞镶嵌
- 批准号:
9212697 - 财政年份:2015
- 资助金额:
$ 23.8万 - 项目类别:
LINE-1 Retrotransposition in Human Embryonic Stem Cells
人类胚胎干细胞中的 LINE-1 逆转座
- 批准号:
7523079 - 财政年份:2008
- 资助金额:
$ 23.8万 - 项目类别:
LINE-1 Retrotransposition in Human Embryonic Stem Cells
人类胚胎干细胞中的 LINE-1 逆转座
- 批准号:
7662421 - 财政年份:2008
- 资助金额:
$ 23.8万 - 项目类别:
LINE-1 Retrotransposition in Human Embryonic Stem Cells
人类胚胎干细胞中的 LINE-1 逆转座
- 批准号:
8072570 - 财政年份:2008
- 资助金额:
$ 23.8万 - 项目类别:
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