Histone Deacetylation Signaling in Aging and Cancer Pathways

我们广泛的研究目标是了解染色质在核和表观遗传中的调节机制 计划以及这些机制是如何在衰老和疾病中放松管制的。一种基本的机制 染色质的调节涉及组蛋白的可逆组蛋白修饰，如乙酰基-， 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和 调节DNA对交易因子的可及性。在萌芽酵母中，组蛋白通过 染色质沉默因子Sir2防止基因组不稳定和衰老，并在哺乳动物中，解除对 组蛋白乙酰化与细胞衰老和衰老相关的病理从神经退变到 癌症。在这里，我们重点研究SIRT7，一个染色质调节的赖氨酸脱乙酰基酶，在Sir2家族中 老龄化--调节因素。本项目将研究SIRT7依赖的组蛋白去乙酰化在 染色质调节机制在衰老和与衰老相关的癌症生物学中被解除调控。 小鼠SIRT7失活会导致基因组不稳定、寿命缩短和衰老相关的表型， 初步研究表明，增加的SIRT7对小鼠的衰老病理具有保护作用。然而， SIRT7还可以支持癌细胞中的致癌转录编程。因此，揭示不同的 SIRT7染色质调节途径可能对剖析SIRT7在衰老中的多效性功能很重要 和癌症途径。最近，我们鉴定了一种新的SIRT7底物，组蛋白H3的乙酰化赖氨酸K36 (H3K36ac)，它在SIRT7失活后显著超乙酰化。H3K36ac涉嫌与 酵母染色质重塑和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-H3K36乙酰化增加- 缺陷细胞与染色质修饰的该残基(H3K36me2)上的二甲基化减少有关 这在基因激活、DNA甲基化和致癌转化中起着重要作用。此外，SIRT7 与癌蛋白NSD2在物理上相互作用，NSD2是许多细胞中产生大量H3K36me2的酶 类型。在这里，我们将研究一种新的模型，SIRT7可以在H3K36上清除大片的 染色质，帮助启动NSD2催化的H3K36甲基化。在目标1中，我们探索了SIRT7的联系 和NSD2在衰老相关过程中的作用，使用基因组、细胞和小鼠系统，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 人类癌症模型。通过发现SIRT7染色质调节的不同途径，该项目可能提示 选择性增强SIRT7在不促进致癌的情况下保护衰老的功能的策略 SIRT7活动。综上所述，这些研究应该能提供对染色质基本机制的洞察。 衰老和癌症生物学。

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.