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
• 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
• 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

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