Progressive DNA Hypomethylation as a Measure of Mitotic History and Potential Contributor to Replicative Senescence.
进行性 DNA 低甲基化作为有丝分裂历史的衡量标准和复制衰老的潜在贡献者。
基本信息
- 批准号:10266860
- 负责人:
- 金额:$ 59.7万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-30 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:AgingAnatomyAttentionAttenuatedAutomobile DrivingBehaviorBiological ClocksBiologyCell AgingCell Culture TechniquesCell CycleCell Cycle InhibitionCell LineCell LineageCell divisionCellsChromatinChronologyCircadian RhythmsComplexContact InhibitionCpG IslandsCpG dinucleotideCuesCytosineDNADNA MaintenanceDNA MethylationDNA Modification MethylasesDNA methyltransferase inhibitionDataDegenerative DisorderDependenceDevelopmentDiseaseEpigenetic ProcessFibroblastsGene ExpressionGenomeGenomicsHealthHistonesHumanIndividualInterventionLinkLocationLongevityMaintenanceMalignant NeoplasmsMeasuresMetabolicMethylationMitosisMitoticModelingMolecularOutcomePhenotypePhysiologicalProcessRecording of previous eventsReportingResearchResistanceRoleSerumTechniquesTelomeraseTestingTimeTissuesbasecell typedeprivationdesignhuman diseasehuman tissueinhibitor/antagonistmolecular clockoverexpressionpremalignantprematurepreventsenescencetoolubiquitin-protein ligase
项目摘要
PROJECT SUMMARY / ABSTRACT
Cellular and molecular alterations that accumulate during cell division are considered to be contributors to
aging phenotypes. Changes in epigenetic marks, including DNA methylation, have been widely documented in
aging. This has spurred the development of epigenetic molecular clocks, which rely primarily on replication-
independent gain of methylation at CpG islands. As molecular clocks tuned to chronological time across
different tissue types with varying mitotic rates and histories, these clocks are not directly linked to mitotic cell
division. In contrast, we have found that loss of DNA methylation at lamina-attached, late-replicating regions of
the genome is closely tied to apparent mitotic history. We propose to use primary human cell culture to
experimentally validate that mitosis is a driver of hypomethylation, and to explore the underlying mechanisms
and consequences of this hypomethylation, to define genomic and chromatin features driving hypomethylation,
and use this data to construct a mitotic molecular clock.
In Specific Aim 1 we propose to use primary human cell culture to provide experimental evidence for the
contribution of mitosis to PMD hypomethylation, and to disentangle the time-dependency and mitosis-
dependency of the phenomenon using cell cycle inhibition. We will also investigate whether enhancing
maintenance methylation machinery is able to counteract the progressive loss of DNA methylation. In Specific
Aim 2 we propose to investigate whether DNA hypomethylation contributes to replicative senescence or
associated phenotypes in primary human cell culture. We will investigate whether inhibition of maintenance
methylation accelerates senescence, and whether progressive hypomethylation is extended in telomerase-
immortalized primary human fibroblasts, contributing to premalignant phenotypes associated with such
immortalization. We will also investigate whether accelerated senescence by progerin expression or supra-
physiologic O2 leads to accelerated DNA hypomethylation. In Specific Aim 3 we will characterize the genomic
and chromatin features that influence individual CpG hypomethylation rates. We will measure the rates of DNA
hypomethylation of individual CpGs in six different primary human cell types and use this information to identify
cell-type-specific, as well as universal genomic and chromatin drivers of hypomethylation. Finally, we will use
elastic net regression on the assembled data to construct cell-type-specific and universal epigenetic mitotic
clocks in Specific Aim 4. The preliminary studies strongly support the concept and feasibility of a DNA
hypomethylation-based mitotic clock. The outcome of this proposed research could have important impacts on
our understanding of the contribution of widespread hypomethylation to aging phenotypes, with potential
implications for aging interventions. The availability of accurate molecular clocks specifically designed to
measure mitotic history would provide a valuable molecular tool to characterize cells and tissues in human
health and disease.
项目摘要/摘要
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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PETER W LAIRD其他文献
PETER W LAIRD的其他文献
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{{ truncateString('PETER W LAIRD', 18)}}的其他基金
Accelerated DNA Methylation Alterations in Hutchinson-Gilford Progeria Syndrome
Hutchinson-Gilford 早衰综合症中 DNA 甲基化的加速改变
- 批准号:
10780718 - 财政年份:2023
- 资助金额:
$ 59.7万 - 项目类别:
Integrative Cancer Epigenomic Data Analysis Center (ICE-DAC)
综合癌症表观基因组数据分析中心(ICE-DAC)
- 批准号:
10301849 - 财政年份:2021
- 资助金额:
$ 59.7万 - 项目类别:
Integrative Cancer Epigenomic Data Analysis Center (ICE-DAC)
综合癌症表观基因组数据分析中心(ICE-DAC)
- 批准号:
10474482 - 财政年份:2021
- 资助金额:
$ 59.7万 - 项目类别:
Integrative Cancer Epigenomic Data Analysis Center (ICE-DAC)
综合癌症表观基因组数据分析中心(ICE-DAC)
- 批准号:
10684894 - 财政年份:2021
- 资助金额:
$ 59.7万 - 项目类别:
Progressive DNA Hypomethylation as a Measure of Mitotic History and Potential Contributor to Replicative Senescence.
进行性 DNA 低甲基化作为有丝分裂历史的衡量标准和复制衰老的潜在贡献者。
- 批准号:
10450874 - 财政年份:2020
- 资助金额:
$ 59.7万 - 项目类别:
Progressive DNA Hypomethylation as a Measure of Mitotic History and Potential Contributor to Replicative Senescence.
进行性 DNA 低甲基化作为有丝分裂历史的衡量标准和复制衰老的潜在贡献者。
- 批准号:
10672187 - 财政年份:2020
- 资助金额:
$ 59.7万 - 项目类别:
Cellular Epigenetic Heterogeneity as a Predeterminant of Malignant Transformation Potential
细胞表观遗传异质性作为恶性转化潜力的决定因素
- 批准号:
10307617 - 财政年份:2018
- 资助金额:
$ 59.7万 - 项目类别:
Cellular Epigenetic Heterogeneity as a Predeterminant of Malignant Transformation Potential
细胞表观遗传异质性作为恶性转化潜力的决定因素
- 批准号:
10533777 - 财政年份:2018
- 资助金额:
$ 59.7万 - 项目类别:
Cellular Epigenetic Heterogeneity as a Predeterminant of Malignant Transformation Potential
细胞表观遗传异质性作为恶性转化潜力的决定因素
- 批准号:
10064579 - 财政年份:2018
- 资助金额:
$ 59.7万 - 项目类别:
Integrative Cancer Epigenomic Data Analysis Center (ICE-DAC)
综合癌症表观基因组数据分析中心(ICE-DAC)
- 批准号:
10005291 - 财政年份:2016
- 资助金额:
$ 59.7万 - 项目类别:
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