Histone Deacetylation Signaling in Aging and Cancer Pathways
衰老和癌症途径中的组蛋白脱乙酰化信号转导
基本信息
- 批准号:10819057
- 负责人:
- 金额:$ 6.59万
- 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:2021-07-09 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:AcetylationAgeAgingAutomobile DrivingBiologyCancer BiologyCell AgingCell physiologyCellsChemicalsChromatinChromatin StructureCoupledDNADNA DamageDNA MethylationDeacetylaseDefectDiseaseEnzymesEpigenetic ProcessFamilyGene ActivationGenetic TranscriptionGenomic InstabilityGenomicsGoalsHistone AcetylationHistone DeacetylationHistone H3HistonesHuman GenomeLinkLongevityLysineMalignant NeoplasmsMammalsMetabolic DiseasesMethylationModelingMusNerve DegenerationNeurodegenerative DisordersNuclearOncogenicOncoproteinsPathologyPathway interactionsPhenotypeProcessRegulationResearchRoleSaccharomycetalesSignal TransductionSystemTestingTherapeutic InterventionTransactYeastscancer cellcell typechromatin modificationchromatin remodelinghistone modificationhuman cancer mouse modelin vivoinsightlung Carcinomanew therapeutic targetnovelpre-clinicalpreventprogramsresponse
项目摘要
Our broad research goal is to understand chromatin regulatory mechanisms in nuclear and epigenetic
programs and how these mechanisms are deregulated in aging and disease. A fundamental mechanism for
regulating chromatin involves the reversible modification of histones by chemical moieties such as acetyl-,
methyl-, and phospho-groups. These different histone marks are linked to discrete chromatin states and
regulate the accessibility of DNA to transacting factors. In budding yeast, histone deacetylation by the
chromatin silencing factor Sir2 prevents genomic instability and aging, and in mammals, de-regulation of
histone acetylation is linked to cellular senescence and aging-related pathologies from neurodegeneration to
cancer. Here, we focus on SIRT7, a chromatin regulatory, lysine deacetylase enzyme in the Sir2 family of
aging-regulatory factors. This project will study new roles of SIRT7-dependent histone deacetylation in
chromatin regulatory mechanisms that are deregulated in aging and age-associated cancer biology.
Inactivation of SIRT7 in mice leads to genomic instability, shortened lifespan and aging-related phenotypes,
and preliminary studies suggest that increased SIRT7 protects against aging pathologies in mice. However,
SIRT7 can also sustain oncogenic transcriptional programming in cancer cells. Thus, uncovering distinct
pathways of SIRT7 chromatin regulation, may be important to dissect pleiotropic functions of SIRT7 in aging
and cancer pathways. Recently, we identified a novel substrate of SIRT7, acetylated lysine K36 of histone H3
(H3K36ac), which is dramatically hyper-acetylated upon SIRT7-inactivation. H3K36ac is implicated in
chromatin remodeling and DNA damage responses in yeast, but its regulation and functions in mammalian
biology are largely obscure. In preliminary studies we found that the increased H3K36 acetylation in SIRT7-
deficient cells is coupled to decreased di-methylation at this residue (H3K36me2), a chromatin modification
that has important roles in gene activation, DNA methylation and oncogenic transformation. Moreover, SIRT7
interacts physically with the oncoprotein NSD2, the enzyme that generates the bulk of H3K36me2 in many cell
types. Here, we will investigate a new model that SIRT7 clears acetylation at H3K36 from large swaths of
chromatin to help prime NSD2-catalyzed methylation at H3K36. In Aim 1, we explore the connection of SIRT7
and NSD2 in aging-related processes using genomic, cellular and mouse systems, and in Aim 2, we test the
role of SIRT7-H3K36-NSD2 methylation axis in driving lung carcinoma in vivo, using pre-clinical mouse and
human cancer models. By uncovering distinct pathways of SIRT7 chromatin regulation, this project may suggst
strategies to selectively enhance functions of SIRT7 that are protective in aging without promoting oncogenic
SIRT7 activities. Together, these studies should provide insights into fundamental chromatin mechanisms in
aging and cancer biology.
我们广泛的研究目标是了解核和表观遗传中的染色质调控机制
程序以及这些机制如何在衰老和疾病中解除管制。一种基本机制,
调节染色质包括通过化学部分如乙酰基-,
甲基和磷酸基。这些不同的组蛋白标记与离散的染色质状态相关,
调节DNA对交易因子的可及性。在芽殖酵母中,
染色质沉默因子Sir 2可防止基因组不稳定性和衰老,在哺乳动物中,
组蛋白乙酰化与细胞衰老和衰老相关的病理学有关,
癌在这里,我们重点关注SIRT 7,它是Sir 2家族中的一种染色质调节性赖氨酸脱乙酰酶。
老化调节因素该项目将研究SIRT 7依赖的组蛋白去乙酰化在
染色质调节机制在衰老和年龄相关的癌症生物学中被解除调节。
SIRT 7在小鼠中的失活导致基因组不稳定、寿命缩短和衰老相关表型,
初步研究表明,增加SIRT 7可以保护小鼠免受衰老病理。然而,在这方面,
SIRT 7还可以维持癌细胞中的致癌转录编程。因此,
SIRT 7染色质调控的途径,可能是重要的解剖多效性功能的SIRT 7在老化
和癌症通路。最近,我们鉴定了SIRT 7的一种新底物,组蛋白H3的乙酰化赖氨酸K36
(H3 K36 ac),其在SIRT 7失活后显著超乙酰化。H3 K36 ac与
酵母中的染色质重塑和DNA损伤反应,但在哺乳动物中的调控和功能
生物学在很大程度上是模糊的。在初步研究中,我们发现SIRT 7 - 100中H3 K36乙酰化的增加,
缺陷细胞与该残基(H3 K36 me 2)的二甲基化降低(染色质修饰)相关联
在基因激活、DNA甲基化和致癌转化中起重要作用。此外,SIRT 7
与癌蛋白NSD 2物理相互作用,NSD 2是在许多细胞中产生大量H3 K36 me 2的酶
类型在这里,我们将研究一个新的模型,SIRT 7清除H3 K36的乙酰化,从大片的
染色质以帮助引发NSD 2催化的H3 K36甲基化。在目标1中,我们探索了SIRT 7
和NSD 2在衰老相关过程中的作用,在目标2中,我们测试了
SIRT 7-H3 K36-NSD 2甲基化轴在体内驱动肺癌中的作用,使用临床前小鼠和
人类癌症模型。通过揭示SIRT 7染色质调控的不同途径,该项目可能会使
选择性增强SIRT 7功能的策略,该功能在衰老中具有保护作用,而不促进致癌性
SIRT 7活动。总之,这些研究应该提供深入了解基本的染色质机制,
衰老和癌症生物学。
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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Katrin F Chua其他文献
Katrin F Chua的其他文献
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{{ truncateString('Katrin F Chua', 18)}}的其他基金
BLRD Research Career Scientist Award Application
BLRD 研究职业科学家奖申请
- 批准号:
10594020 - 财政年份:2022
- 资助金额:
$ 6.59万 - 项目类别:
Histone Deacetylation Signaling in Aging and Cancer Pathways
衰老和癌症途径中的组蛋白脱乙酰化信号转导
- 批准号:
10651829 - 财政年份:2021
- 资助金额:
$ 6.59万 - 项目类别:
Histone Deacetylation Signaling in Aging and Cancer Pathways
衰老和癌症途径中的组蛋白脱乙酰化信号转导
- 批准号:
10448391 - 财政年份:2021
- 资助金额:
$ 6.59万 - 项目类别:
Molecular Mechanisms of Mammalian SIRT6 Function
哺乳动物 SIRT6 功能的分子机制
- 批准号:
9282767 - 财政年份:2016
- 资助金额:
$ 6.59万 - 项目类别:
Molecular Mechanisms of Mammalian SIRT6 Function
哺乳动物 SIRT6 功能的分子机制
- 批准号:
9107282 - 财政年份:2016
- 资助金额:
$ 6.59万 - 项目类别:
Molecular Mechanisms of Mammalian SIRT6 Function
哺乳动物 SIRT6 功能的分子机制
- 批准号:
9901411 - 财政年份:2016
- 资助金额:
$ 6.59万 - 项目类别:
Molecular Mechanisms of Mammalian SIRT6 Function
哺乳动物 SIRT6 功能的分子机制
- 批准号:
9118549 - 财政年份:2015
- 资助金额:
$ 6.59万 - 项目类别:
MOLECULAR INTERACTIONS AND SUBSTRATES OF MAMMALIAN SIRT6 LONGEVITY REGULATOR
哺乳动物 SIRT6 寿命调节剂的分子相互作用和底物
- 批准号:
8363767 - 财政年份:2011
- 资助金额:
$ 6.59万 - 项目类别:
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