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:10450874
- 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 tissueinhibitormolecular 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.
项目总结/摘要
在细胞分裂过程中积累的细胞和分子改变被认为是
衰老表型表观遗传标记的变化,包括DNA甲基化,已被广泛记录,
衰老这刺激了表观遗传分子钟的发展,它主要依赖于复制-
CpG岛甲基化的独立获得。当分子钟调整到按时间顺序排列时,
不同的组织类型具有不同的有丝分裂速率和历史,这些时钟与有丝分裂细胞没有直接联系。
师.与此相反,我们发现,DNA甲基化的损失,在板层连接,后期复制的区域,
基因组与明显的有丝分裂历史密切相关。我们建议使用原代人类细胞培养,
实验验证有丝分裂是低甲基化的驱动因素,并探索潜在的机制
以及这种低甲基化的后果,以定义驱动低甲基化的基因组和染色质特征,
并利用这些数据来构建一个有丝分裂分子钟。
在具体目标1中,我们建议使用原代人类细胞培养来提供实验证据,
有丝分裂对PMD低甲基化的贡献,并解开时间依赖性和有丝分裂-
使用细胞周期抑制的现象的依赖性。我们还将研究是否增强
维持甲基化机制能够抵消DNA甲基化的进行性丧失。在特定
目的2:研究DNA低甲基化是否参与复制性衰老,
在原代人细胞培养物中的相关表型。我们将研究是否抑制维持
甲基化加速衰老,以及进行性低甲基化是否在端粒酶中延长,
永生化的原代人成纤维细胞,有助于与这种细胞相关的癌前表型。
永生我们还将研究是否加速衰老的早老蛋白表达或超-
生理性O2导致加速的DNA低甲基化。在具体目标3中,我们将描述基因组
以及影响个体CpG低甲基化率的染色质特征。我们将测量DNA的比率
在六种不同的原代人类细胞类型中的单个CpG的低甲基化,并使用该信息来鉴定
细胞类型特异性,以及低甲基化的通用基因组和染色质驱动因素。最后,我们将使用
弹性网络回归的组装数据,以构建细胞类型特异性和通用的表观遗传有丝分裂
特定目标4中的时钟。初步研究有力地支持了DNA的概念和可行性
基于低甲基化有丝分裂时钟。这项研究的结果可能会产生重要影响,
我们对广泛的低甲基化对衰老表型的贡献的理解,
对老龄化干预的影响。精确的分子钟的可用性,
测量有丝分裂史将为表征人类细胞和组织提供有价值的分子工具
健康和疾病。
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:
10672187 - 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:
10266860 - 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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