Chromatin diminution in nematodes
线虫中的染色质减少
基本信息
- 批准号:9204381
- 负责人:
- 金额:$ 57.49万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-08-20 至 2020-01-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAreaAscarisAscaris suumBiologicalBiologyCell LineageCell NucleusCellsCentromereChIP-seqChromatinChromosomal BreaksChromosome SegregationChromosome StructuresChromosomesComplexDNADNA SequenceDataDepositionDevelopmentDrug TargetingEmbryoEukaryotaGene ExpressionGenesGenomeGenome StabilityHistone H3HumanImmunohistochemistryKinetochoresLengthLocationMaintenanceMicrotubulesMitosisNematodaNuclearOrganismParasitesParasitic nematodePathogenesisPathway interactionsPharmacotherapyPlayProcessPropertyProteinsPublic HealthResourcesRoleSiteSmall RNASomatic CellTestingTissuesVariantbasecentromere protein Achromosomal locationexperimental studyinsightneuronal cell bodynew technologynew therapeutic targetnovelpathogenpublic health relevancesegregationsocioeconomicstool
项目摘要
DESCRIPTION (provided by applicant): Ascaris is an important human pathogen infecting ~1 billion people. Understanding genome maintenance, genome alterations, and the role of these alterations in gene expression in Ascaris is important for understanding its biology and pathogenesis. Genomes rarely change. However, a few organisms undergo the wholesale genome change called chromatin diminution, a programmed process that eliminates specific DNA sequences from the genome. Many aspects of the phenomenon remain a mystery. We previously leveraged new technologies to characterize chromatin diminution in the parasitic nematode, Ascaris, We demonstrated that thirteen percent of the genome of the parasitic nematode Ascaris suum is eliminated in somatic cell lineages during the third through fifth cleavage (4 to 16 cell stage), while the germline genome remains intact. Unique sequences (including ~700 genes) are lost during chromatin diminution to form the somatic genome. The eliminated genes we identified are primarily expressed in the Ascaris germline and early embryo. This leads us to suggest that chromatin diminution in Ascaris is the essential, irreversible mechanism for silencing a subset of germline and early embryo expressed genes in somatic tissues required for distinguishing between the germline and soma. More than 100 years after it was first discovered, the mechanisms for how specific Ascaris chromosomal regions are targeted and selected for elimination or retention remain unknown. Two key mechanistic questions are: 1) How are the locations of the chromosomal breaks and boundary regions identified, marked, and cut? 2) What determines which chromosomal regions are retained or lost? We have formulated hypotheses regarding these key questions based on our preliminary data and propose to test these hypotheses in the specific aims. In preliminary experiments, we have shown that during Ascaris chromatin diminution, only those chromosomes that will be retained have extensive deposition of CENP-A (the key factor required for centromere formation and kinetochore assembly), whereas chromosomes destined for elimination have little CENP-A. This suggests a potential mechanistic explanation for how specific portions of chromosomes can be marked for retention or elimination. We propose to investigate the deposition and role of CENP-A as a mechanism for differential chromosome segregation in chromatin diminution. We further hypothesize that small RNAs and Argonautes play a role in Ascaris chromatin diminution. We have shown that specialized Argonautes associate with chromosomes that will be retained in Ascaris diminution mitosis, but not with chromosomes that are destined for elimination. We propose to investigate the role of these Argonautes and their associated small RNAs in nematode chromatin diminution and chromosome segregation. Analysis of Ascaris chromatin diminution promises to provide profound insights into genome stability, centromere specification, chromosome segregation and the contribution of Argonautes and small RNAs to chromosome function, segregation, and chromatin diminution. Our studies will not only provide insight into DNA elimination and its importance in nematodes, but is likely to increase our understanding of the germline, chromosomes, and genome biology in general. Finally, a better understanding of Ascaris chromosome organization and segregation and its small RNA pathways that differ from its human host may provide new insight into needed drug targets.
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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RICHARD E. DAVIS其他文献
RICHARD E. DAVIS的其他文献
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{{ truncateString('RICHARD E. DAVIS', 18)}}的其他基金
11th Molecular and Cellular Biology of Helminth Parasites Meeting
第11届蠕虫寄生虫分子和细胞生物学会议
- 批准号:
9259055 - 财政年份:2017
- 资助金额:
$ 57.49万 - 项目类别:
Structural Analysis of Helminth mRNA Cap-Binding Proteins
蠕虫 mRNA 帽结合蛋白的结构分析
- 批准号:
7659946 - 财政年份:2009
- 资助金额:
$ 57.49万 - 项目类别:
Structural Analysis of Helminth mRNA Cap-Binding Proteins
蠕虫 mRNA 帽结合蛋白的结构分析
- 批准号:
7768502 - 财政年份:2009
- 资助金额:
$ 57.49万 - 项目类别:
IN VIVO ANALYSIS OF SL ADDITION IN ASCARIS EMBRYOS
蛔虫胚胎中 SL 添加的体内分析
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6615690 - 财政年份:2000
- 资助金额:
$ 57.49万 - 项目类别:
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