Epigenetic Regulation of Inflammatory Gene Expression by Telomerase

描述(申请人提供)：先天性免疫反应是动脉粥样硬化性心血管疾病发病机制的核心，通过涉及染色质结构的表观遗传修饰的转录网络来协调。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(TERT)除了在染色体末端合成端粒重复序列的功能外，还在促进基因激活方面发挥直接作用 表情程序。TERT在允许基因转录方面的第二个活性似乎独立于其在端粒动态平衡中的作用，但可能涉及到对高阶染色质结构的修饰。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可以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改变巨噬细胞炎症基因的表达，使人联想到基因沉默。为了探讨这些发现的意义，并验证TERT通过表观遗传的染色质修饰促进巨噬细胞炎症基因表达并促进动脉粥样硬化发展的假说，提出了两个特定的目标。在具体目标1中，我们将利用细胞和分子方法相结合的方法来确定TERT调节巨噬细胞炎症基因表达程序的转录机制。在特定的目标2中，我们将确定TERT在动脉粥样硬化发展中的作用，并验证TERT依赖的巨噬细胞炎症基因表达激活构成疾病发展的重要机制的假说。最终，这些研究结果不仅将TERT作为染色质修饰物和新的调节蛋白来协调巨噬细胞炎症基因的表达，而且还将促进我们对导致动脉粥样硬化发展的炎症机制的理解。

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.