MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou 510006, P.R. China.
Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China.
Nucleic Acids Res. 2019 Sep 5;47(15):8084-8095. doi: 10.1093/nar/gkz584.
TERC is an RNA component of telomerase. However, TERC is also ubiquitously expressed in most human terminally differentiated cells, which don't have telomerase activity. The function of TERC in these cells is largely unknown. Here, we report that TERC enhances the expression and secretion of inflammatory cytokines by stimulating NK-κB pathway in a telomerase-independent manner. The ectopic expression of TERC in telomerase-negative cells alters the expression of 431 genes with high enrichment of those involved in cellular immunity. We perform genome-wide screening using a previously identified 'binding motif' of TERC and identify 14 genes that are transcriptionally regulated by TERC. Among them, four genes (LIN37, TPRG1L, TYROBP and USP16) are demonstrated to stimulate the activation of NK-κB pathway. Mechanistically, TERC associates with the promoter of these genes through forming RNA-DNA triplexes, thereby enhancing their transcription. In vivo, expression levels of TERC and TERC target genes (TYROBP, TPRG1L and USP16) are upregulated in patients with inflammation-related diseases such as type II diabetes and multiple sclerosis. Collectively, these results reveal an unknown function of TERC on stimulating inflammatory response and highlight a new mechanism by which TERC modulates gene transcription. TERC may be a new target for the development of anti-inflammation therapeutics.
TERC 是端粒酶的 RNA 成分。然而，TERC 也在大多数人类终末分化细胞中广泛表达，这些细胞没有端粒酶活性。TERC 在这些细胞中的功能很大程度上是未知的。在这里，我们报告 TERC 通过非依赖端粒酶的方式刺激 NK-κB 通路来增强炎症细胞因子的表达和分泌。TERC 在端粒酶阴性细胞中的异位表达改变了 431 个基因的表达，这些基因高度富集于细胞免疫相关基因。我们使用先前鉴定的 TERC 的“结合基序”进行全基因组筛选，鉴定出 14 个受 TERC 转录调控的基因。其中，四个基因（LIN37、TPRG1L、TYROBP 和 USP16）被证明能刺激 NK-κB 通路的激活。在机制上，TERC 通过形成 RNA-DNA 三链体与这些基因的启动子结合，从而增强它们的转录。在体内，炎症相关疾病（如 2 型糖尿病和多发性硬化症）患者的 TERC 和 TERC 靶基因（TYROBP、TPRG1L 和 USP16）的表达水平上调。总之，这些结果揭示了 TERC 刺激炎症反应的未知功能，并强调了 TERC 调节基因转录的新机制。TERC 可能是开发抗炎治疗的新靶点。
