Epigenetic Regulation of Inflammatory Gene Expression by Telomerase

描述（由申请人提供）：先天免疫应答是动脉粥样硬化性心血管疾病发病机制的核心，并通过涉及染色质结构表观遗传修饰的转录网络进行协调。现在有越来越多的证据表明，染色质状态受到端粒酶的影响。端粒酶逆转录酶（telomerase reverse transcriptase，TERT）除了在染色体末端合成端粒重复序列外，还直接促进基因的激活， 表达程序。这第二个活动的端粒酶逆转录酶在允许基因转录似乎独立于其在端粒稳态的作用，但可能涉及更高层次的染色质结构的修改。尽管TERT在人类动脉粥样硬化病变的巨噬细胞中表达，但这种非典型的TERT活性在炎症和动脉粥样硬化中的生理作用仍有待发现。我们最近的研究证实，TERT激活巨噬细胞中的基因启动子。相反，TERT缺陷通过诱导染色质修饰使人联想到基因沉默来改变巨噬细胞炎性基因表达。提出了两个具体的目标，以探索这些发现的意义，并测试的假设，即TERT促进炎症基因表达的巨噬细胞通过表观遗传染色质修饰，并有助于动脉粥样硬化的发展。在特定目标1中，我们将利用细胞和分子方法的组合来确定TERT调节巨噬细胞炎症基因表达程序的转录机制。在具体目标2中，我们将确定TERT对动脉粥样硬化发展的贡献，并检验巨噬细胞中炎症基因表达的TERT依赖性激活构成疾病发展的重要机制的假设。最终，这些研究的结果将不仅表征作为染色质修饰剂和新的调控蛋白协调巨噬细胞炎症基因的表达，但也推进了我们的炎症机制的理解，有助于动脉粥样硬化的发展。 公共卫生相关性：在美国，动脉粥样硬化性心血管疾病是导致死亡的主要原因，并且炎症途径导致疾病的所有阶段。本申请将研究控制动脉粥样硬化形成过程中炎症激活的新机制。这些研究的结果可能最终表征导致血管疾病的新途径，并带来新的治疗机会。

DESCRIPTION (provided by applicant): Innate immune responses are central to the pathogenesis of atherosclerotic cardiovascular disease and are orchestrated through transcriptional networks involving epigenetic modification of the chromatin architecture. There is now increasing evidence that the chromatin state is affected by telomerase. In addition to its well- established function to synthesize telomere repeats at the ends of chromosomes, telomerase reverse transcriptase (TERT) serves a direct role in facilitating the activation of gene expression programs. This second activity of TERT in permitting gene transcription appears to operate independently of its role in telomere homeostasis but may involve modification of the higher-order chromatin structure. Although TERT is expressed in macrophages of human atherosclerotic lesions, a physiological role of this non-canonical activity of TERT in inflammation and atherosclerosis remains to be discovered. Our recent studies confirmed that TERT activates gene promoters in macrophages. Conversely, TERT-deficiency alters macrophage inflammatory gene expression by inducing chromatin modifications reminiscent of gene silencing. Two specific aims are proposed to explore the significance of these findings and to test the hypothesis that TERT promotes inflammatory gene expression in macrophages through epigenetic chromatin modifications and contributes to the development of atherosclerosis. In Specific Aim 1 we will utilize a combination of cellular and molecular approaches to determine the transcriptional mechanisms by which TERT regulates macrophage inflammatory gene expression programs. In Specific Aim 2 we will determine the contribution of TERT to the development of atherosclerosis and test the hypothesis that TERT-dependent activation of inflammatory gene expression in macrophages constitutes an important mechanism for the development of the disease. Ultimately, the results of these studies will not only characterize TERT as a chromatin modifier and novel regulatory protein orchestrating macrophage inflammatory gene expression but also advance our understanding of the inflammatory mechanisms contributing to the development of atherosclerosis. PUBLIC HEALTH RELEVANCE: Atherosclerotic cardiovascular disease is the leading cause of death in the United States, and inflammatory pathways contribute to all stages of the disease. This application will investigate novel mechanisms that control the activation of inflammation during atherosclerosis formation. The results of these studies may ultimately characterize novel pathways contributing to vascular diseases and lead to new therapeutic opportunities.