Chromatin regulation by human SIRT7 in aging-associated cellular programs

6.项目总结/摘要 SIRTUIN（SIRT）基因通过调节基因组结构来调节多种生物体的衰老和寿命。 稳定性、抗应激性和新陈代谢。在哺乳动物中，SIRTUIN基因SIRT 7与衰老有多种联系 与年龄有关的疾病。SIRT 7与心脏中的细胞死亡、应激抗性和炎症有关 组织，SIRT 7突变小鼠患有炎性和退行性心脏病。SIRT 7在一个 一个经常发生突变的染色体区域，包括急性白血病、淋巴瘤和其他与衰老相关的 癌症，并且SIRT 7蛋白水平在肿瘤组织中增加。因此，SIRT 7与多种生理学相关。 以及直接影响退伍军人健康的疾病过程。尽管这些重要的联系， SIRT 7在人类疾病过程中的作用，目前对其分子作用机制的了解相对较少。 这项研究旨在阐明SIRT 7的机制。这项工作将调查的假设 SIRT 7通过一种新的生物化学机制对衰老和癌症相关的细胞程序产生影响， 染色质是哺乳动物基因组DNA包装的分子结构。很长的- 本研究的长期目标是阐明细胞内染色质调节的分子途径， SIRT 7影响癌症、代谢和其他与年龄相关的病理，并识别细胞程序， 可以作为治疗干预的目标。随着越来越多的老年退伍军人，这些研究应该 与生物医学进步高度相关，以造福退伍军人的健康。 具体目的I：阐明SIRT 7在基因组稳定和DNA损伤反应中的作用。 DNA损伤和遗传毒性应激的环境和代谢来源有助于基因组不稳定性， 老化和与年龄相关的组织变性和病理学。初步数据表明，SIRT 7影响 通过染色质的新酶活性对遗传毒性应激的细胞反应。生化、细胞 生物学和细胞遗传学方法将被用来定义SIRT 7的作用和作用机制， 基因组稳定、DNA损伤信号和DNA修复。 具体目的II：阐明SIRT 7在细胞衰老中的功能。 细胞衰老程序是由端粒功能障碍、DNA损伤、激活的癌基因和 癌症和衰老背景下的其他细胞压力。在初步工作中，SIRT 7失活导致 过早衰老将进行功能和生物化学研究，以确定分子 SIRT 7在细胞衰老中功能的机制和生理背景。 具体目的III：鉴定和表征SIRT 7在基因表达网络和核表达调控中的功能。 表观遗传衰老相关细胞程序中的信号通路。 特化染色质状态的建立在细胞基因的表观遗传调控中起着重要作用 表达程序，影响衰老和癌症的分子途径。候选数量基因 表达分析结合途径特异性阵列方法将用于鉴定 SIRT 7依赖的染色质调节。重点将放在表观遗传基因表达程序 与DNA损伤反应、细胞衰老和细胞转化相关。

6. Project Summary/Abstract SIRTUIN (SIRT) genes modulate aging and lifespan in multiple organisms, through regulation of genomic stability, stress-resistance, and metabolism. In mammals, the SIRTUIN gene SIRT7 has multiple links to aging and age-related disease. SIRT7 is implicated in cell death, stress resistance, and inflammation in cardiac tissue, and SIRT7 mutant mice suffer from inflammatory and degenerative cardiac disease. SIRT7 is on a chromosomal region that is frequently mutated acute leukemia, lymphoma, and other aging-associated cancers, and SIRT7 protein levels are increased in tumor tissues. Thus, SIRT7 is linked to multiple physiologic and disease processes that directly impact on the health of the veterans. Despite these important links of SIRT7 to human disease processes, relatively little is understood about its molecular mechanisms of action. The research proposed here aims to elucidate SIRT7 mechanisms. The work will investigate the hypothesis that SIRT7 exerts effects on aging- and cancer- associated cellular programs through a novel biochemical activity at chromatin, the molecular structure in which the DNA of mammalian genomes is packaged. The long- term goals of the research are to elucidate the molecular pathways through which chromatin regulation by SIRT7 influences cancer, metabolism, and other age-related pathologies, and identify cellular programs that can be targeted for therapeutic intervention. With the growing numbers of aging veterans, these studies should be highly relevant for biomedical advancements to benefit veterans' health. Specific Aim I: To elucidate the role of SIRT7 in genome stabilization and DNA damage responses. Environmental and metabolic sources of DNA damage and genotoxic stress contribute to genomic instability, aging, and age-related tissue degeneration and pathologies. Preliminary data suggest that SIRT7 influences cellular responses to genotoxic stress through a novel enzymatic activity at chromatin. Biochemical, cell biological, and cytogenetic approaches will be used to define the role and mechanisms of action of SIRT7 in genome stabilization, DNA damage signaling, and DNA repair. Specific Aim II: To elucidate the function of SIRT7 in cellular senescence. Cellular senescence programs are triggered by telomere dysfunction, DNA damage, activated oncogenes, and other cellular stresses in the contexts of cancer and aging. In preliminary work, SIRT7 inactivation leads to premature senescence. Functional and biochemical studies will be carried out to determine the molecular mechanisms and physiologic contexts of SIRT7 function in cellular senescence. Specific Aim III: To identify and characterize the function of SIRT7 in gene expression networks and nuclear signaling pathways in epigenetic aging-associated cellular programs. Establishment of specialized chromatin states plays important roles in epigenetic regulation of cellular gene expression programs that impact on molecular pathways in aging and cancer. Candidate quantitative gene expression analysis coupled with pathway-specific array approaches will be used to identify gene targets of SIRT7-dependent chromatin regulation. Focus will be placed on epigenetic gene expression programs associated with DNA damage responses, cellular senescence, and cellular transformation.