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: 10819057
• 负责人: Katrin F Chua
• 金额: $ 6.59万
• 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/10819057
• 关键词: Acetylation; Age; Aging; Automobile Driving; Biology; Cancer Biology; Cell Aging; Cell physiology; Cells; Chemicals; Chromatin; Chromatin Structure; Coupled; DNA; DNA Damage; DNA Methylation; Deacetylase; Defect; Disease; Enzymes; Epigenetic Process; Family; Gene Activation; Genetic Transcription; Genomic Instability; Genomics; Goals; Histone Acetylation; Histone Deacetylation; Histone H3; Histones; Human Genome; Link; Longevity; Lysine; Malignant Neoplasms; Mammals; Metabolic Diseases; Methylation; Modeling; Mus; Nerve Degeneration; Neurodegenerative Disorders; Nuclear; Oncogenic; Oncoproteins; Pathology; Pathway interactions; Phenotype; Process; Regulation; Research; Role; Saccharomycetales; Signal Transduction; System; Testing; Therapeutic Intervention; Transact; Yeasts; cancer cell; cell type; chromatin modification; chromatin remodeling; histone modification; human cancer mouse model; in vivo; insight; lung Carcinoma; new therapeutic target; novel; pre-clinical; prevent; programs; response

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 计划以及这些机制如何在衰老和疾病中放松管制。一个基本机制 调节染色质涉及通过乙酰基等化学部分对组蛋白进行可逆修饰， 甲基和磷酸基团。这些不同的组蛋白标记与离散的染色质状态有关 调节 DNA 对交易因子的可及性。在芽殖酵母中，组蛋白脱乙酰化 染色质沉默因子 Sir2 可防止基因组不稳定和衰老，并且在哺乳动物中， 组蛋白乙酰化与细胞衰老和衰老相关病理有关，从神经退行性变到 癌症。在这里，我们重点关注 SIRT7，这是 Sir2 家族中的一种染色质调节赖氨酸脱乙酰酶。 衰老调节因素。该项目将研究 SIRT7 依赖性组蛋白脱乙酰化在 在衰老和与年龄相关的癌症生物学中失调的染色质调节机制。 小鼠体内 SIRT7 失活会导致基因组不稳定、寿命缩短和衰老相关表型， 初步研究表明，SIRT7 的增加可以防止小鼠出现衰老病症。然而， SIRT7 还可以维持癌细胞中的致癌转录编程。因此，揭示了不同的 SIRT7 染色质调节途径，对于剖析 SIRT7 在衰老过程中的多效性功能可能很重要 和癌症途径。最近，我们鉴定了 SIRT7 的一个新底物，组蛋白 H3 的乙酰化赖氨酸 K36 (H3K36ac)，SIRT7 失活后显着高度乙酰化。 H3K36ac 涉及 酵母中的染色质重塑和 DNA 损伤反应，但其在哺乳动物中的调节和功能 生物学在很大程度上是晦涩难懂的。在初步研究中，我们发现 SIRT7- 中 H3K36 乙酰化增加 缺陷细胞与该残基 (H3K36me2) 的二甲基化减少有关，这是一种染色质修饰 在基因激活、DNA甲基化和致癌转化中具有重要作用。此外，SIRT7 与癌蛋白 NSD2 发生物理相互作用，NSD2 是在许多细胞中产生大量 H3K36me2 的酶 类型。在这里，我们将研究 SIRT7 从大范围的 H3K36 处清除乙酰化的新模型 染色质有助于引发 NSD2 催化的 H3K36 甲基化。在目标 1 中，我们探索 SIRT7 的连接 和 NSD2 使用基因组、细胞和小鼠系统参与衰老相关过程，在目标 2 中，我们测试了 SIRT7-H3K36-NSD2 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 SIRT7 染色质调节的不同途径，该项目可能表明 选择性增强 SIRT7 功能的策略，这些功能具有衰老保护作用，但不会促进致癌 SIRT7 活动。总之，这些研究应该提供对染色质基本机制的见解。 衰老和癌症生物学。