Epigenetic Regulation of Inflammatory Gene Expression by Telomerase

描述（由申请人提供）：先天免疫反应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编排。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）除了具有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起着直接作用

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.