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：
10448391
负责人：
Katrin F Chua
金额：
$ 44.56万
依托单位：
PALO ALTO VETERANS INSTIT FOR RESEARCH
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：
https://reporter.nih.gov/project-details/10448391
关键词：
Acetylation Age Aging Attenuated Automobile Driving Biochemical Biology Biology of Aging Cancer Biology Cancer Etiology Cancer Model Cancer cell line Cell Aging Cell physiology Cells Cessation of life Chemicals Chromatin Chromatin Structure Coupled Coupling DNA DNA Damage DNA Methylation Deacetylase Deacetylation Defect Disease Enzymes Epigenetic Process Event Family Gene Activation Generations Genetic Models Genetic Transcription Genome Genomic Instability Genomics Goals Histone Acetylation Histone Deacetylation Histone H3 Histones Human Human Genome KRAS2 gene Lead Link Location Longevity Lung Adenocarcinoma Lysine Malignant - descriptor Malignant Neoplasms Mammalian Cell Mammals Mediating Metabolic Diseases Methylation Modeling Molecular Mus Mutation Nerve Degeneration Neurodegenerative Disorders Non-Small-Cell Lung Carcinoma Nuclear Oncogenic Oncoproteins Pathology Pathway interactions Phenocopy Phenotype Premature aging syndrome Process Proteins Regulation Research Resistance Role Saccharomycetales Signal Pathway Signal Transduction Study models Survival Rate System Testing Therapeutic Intervention Transact United States Work Yeasts cancer cell cell type chromatin modification chromatin remodeling epigenomics histone modification in vivo insight lung Carcinoma mouse model neoplastic new therapeutic target novel overexpression pre-clinical prevent programs protective effect response restoration senescence tumor tumorigenesis

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学中的染色质调节机制程序以及这些机制如何在衰老和疾病中放松管制。一种基本机制调节染色质涉及化学部分对组蛋白的可逆修饰，例如乙酰基，甲基和磷酸组。这些不同的组蛋白标记与离散的染色质状态和调节DNA对交易因子的可及性。在萌芽的酵母中，组蛋白通过染色质沉默因子SIR2阻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与衰老相关的病理有关癌症。在这里，我们专注于SIRT7，这是一种染色质调节性的赖氨酸脱乙酰基酶老化调节因素。该项目将研究SIRT7依赖性组蛋白脱乙酰基的新作用染色质调节机制在衰老和与年龄相关的癌症生物学中受管制。小鼠中SIRT7的失活导致基因组不稳定性，寿命缩短和与衰老相关的表型，初步研究表明，增加的SIRT7可防止小鼠衰老的病理。然而， SIRT7还可以在癌细胞中维持致癌转录编程。因此，发现独特的 SIRT7染色质调节的途径对于剖析衰老中SIRT7的多效函数可能很重要和癌症途径。最近，我们鉴定了一种新型SIRT7的基材，组蛋白H3的乙酰化赖氨酸K36 （H3K36AC），在SIRT7灭活后被大大乙酰化。 H3K36AC与酵母中的染色质重塑和DNA损伤反应，但其调节和功能在哺乳动物中生物学在很大程度上晦涩难懂。在初步研究中，我们发现SIRT7-中H3K36乙酰化增加了缺乏细胞在该残基（H3K36ME2）（染色质修饰）处偶联到二甲基化降低这在基因激活，DNA甲基化和致癌转化中具有重要作用。而且，Sirt7 与癌蛋白NSD2进行物理相互作用，该酶在许多细胞中生成大部分H3K36me2的酶类型。在这里，我们将调查一种新模型，该模型SIRT7从大量大小的大小中清除H3K36的乙酰化在H3K36时，染色质有助于NSD2催化的甲基化。在AIM 1中，我们探索SIRT7的联系使用基因组，细胞和小鼠系统的衰老相关过程中的NSD2，在AIM 2中，我们测试 SIRT7-H3K36-NSD2甲基化轴的作用在体内驱动肺癌，使用前小鼠和人类癌症模型。通过发现SIRT7染色质调节的不同途径，该项目可能会建议选择性增强SIRT7功能的策略，这些功能在衰老中具有保护性而无需促进致癌 SIRT7活动。这些研究共同提供了对基本染色质机制的见解衰老和癌症生物学。