Loss of transcriptional homeostasis of genes lacking CpG islands during aging
衰老过程中缺乏 CpG 岛的基因转录稳态丧失
基本信息
- 批准号:10488179
- 负责人:
- 金额:$ 47.02万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-15 至 2022-09-30
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAddressAgeAge of OnsetAgingArchitectureAutomobile DrivingBromodomainCaenorhabditis elegansCardiomyopathiesCell AgingCell NucleusCellsChromatinChronicComputer AnalysisCpG IslandsDataDeteriorationDevelopmentDiseaseEchocardiographyElementsExhibitsFunctional disorderGene ExpressionGene SilencingGenesGenetic TranscriptionHeartHeterochromatinHistologyHomeostasisHumanImmuneImmunofluorescence ImmunologicInflammationInflammatoryLongevityMediatingMusNoiseNuclearNuclear LaminaOncogene DeregulationOrganPathologyPatternPharmacologyPhysiologicalPlasmaPremature aging syndromeProtein FamilyProteomePulmonary FibrosisRNAReportingResearchStrokeSystemTestingTimeTissuesage relatedagedcytokinedrug repurposingfrailtyin silicoindexinginhibitorinnovationischemic cardiomyopathymRNA sequencingmouse modelnovelpromotersingle-cell RNA sequencingsystemic inflammatory responsetherapeutically effective
项目摘要
PROJECT SUMMARY/ABSTRACT
Changes in chromatin architecture is a hallmark of aging. Disruption of the nuclear lamina and associated
heterochromatin are commonly observed in various aging contexts, including premature aging diseases, cellular
senescence, and normative aging. Although these shared structural changes have been reported for over two
decades, their impact on transcription and the contribution to age-related degenerative changes remains
unknown. Through computational analysis, we recently identified that CpG islands (CGIs), mammalian
promoter-associated elements, provide important clues to answering this question. In humans, about 60% of
genes contain CGIs at their promoters (CGI+ genes) and are broadly expressed throughout the body, while the
other 40% of genes that do not have CGIs (CGI- genes) exhibit tissue-restricted expression patterns. Our
preliminary results demonstrate that, in young nuclei, only CGI- genes can reside within lamina-associated
heterochromatin, when transcriptionally inactive. This suggests that aging-mediated heterochromatin
decondensation and lamina disruption would specifically hinder the repressive status of CGI- genes. Our data
indeed show over 30% of CGI- genes are mis-activated within various aged tissues, and this pattern coincides
with the loss of organ function. In this project, we will test the novel hypothesis that 1) changes in chromatin
architecture during aging directly trigger uncontrolled expression of CGI- genes in tissues/contexts where they
should not be expressed and this, in turn, 2) accelerates age-associated deterioration. We will also test whether
the 3) pharmacological inhibition of CGI- gene misexpression delay age-related degenerative changes.
项目摘要/摘要
染色质结构的变化是衰老的标志。核层的破坏和相关
异染色质通常在各种衰老环境中观察到,包括早衰病、细胞
衰老,和正常衰老。尽管这些共同的结构变化已经报道了两个多月
几十年来,它们对转录的影响以及对年龄相关退行性变化的贡献仍然存在
未知。通过计算分析,我们最近发现CpG岛(CGI),哺乳动物
启动子相关元件,为回答这个问题提供了重要线索。在人类中,大约60%的
基因在其启动子(CGI+基因)处含有CGI,并在全身广泛表达,而
其他40%没有CGI(CGI基因)的基因表现出组织限制性表达模式。我们的
初步结果表明,在年轻的细胞核中,只有cgi基因可以驻留在与膜相关的膜内。
异染色质,当转录不活跃时。这表明,衰老介导的异染色质
解凝集和椎板破坏会特别阻碍CGI基因的抑制状态。我们的数据
确实表明超过30%的CGI基因在各种衰老组织中被错误激活,这一模式与此相吻合
器官功能的丧失。在这个项目中,我们将检验新的假设:1)染色质的变化
衰老过程中的结构直接触发CGI基因在组织/上下文中的不受控制的表达
不应该表达,这反过来又会加速与年龄相关的恶化。我们还将测试
3)对CGI基因错误表达的药理抑制延缓了与年龄相关的退行性改变。
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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Samuel Beck其他文献
Samuel Beck的其他文献
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{{ truncateString('Samuel Beck', 18)}}的其他基金
Chromatin architecture disruption and the vicious cycle of aging.
染色质结构破坏和衰老的恶性循环。
- 批准号:
10901040 - 财政年份:2023
- 资助金额:
$ 47.02万 - 项目类别:
Loss of transcriptional homeostasis of genes lacking CpG islands during aging
衰老过程中缺乏 CpG 岛的基因转录稳态丧失
- 批准号:
10814562 - 财政年份:2023
- 资助金额:
$ 47.02万 - 项目类别:
Loss of transcriptional homeostasis of genes lacking CpG islands during aging
衰老过程中缺乏 CpG 岛的基因转录稳态丧失
- 批准号:
10209189 - 财政年份:2021
- 资助金额:
$ 47.02万 - 项目类别:
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