Department of Medicine, University of California, San Diego, La Jolla, CA.
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA.
J Exp Med. 2022 Jun 6;219(6). doi: 10.1084/jem.20211756. Epub 2022 May 20.
During an immune response to microbial infection, CD8+ T cells give rise to short-lived effector cells and memory cells that provide sustained protection. Although the transcriptional programs regulating CD8+ T cell differentiation have been extensively characterized, the role of long noncoding RNAs (lncRNAs) in this process remains poorly understood. Using a functional genetic knockdown screen, we identified the lncRNA Malat1 as a regulator of terminal effector cells and the terminal effector memory (t-TEM) circulating memory subset. Evaluation of chromatin-enriched lncRNAs revealed that Malat1 grouped with trans lncRNAs that exhibit increased RNA interactions at gene promoters and gene bodies. Moreover, we observed that Malat1 was associated with increased H3K27me3 deposition at a number of memory cell-associated genes through a direct interaction with Ezh2, thereby promoting terminal effector and t-TEM cell differentiation. Our findings suggest an important functional role of Malat1 in regulating CD8+ T cell differentiation and broaden the knowledge base of lncRNAs in CD8+ T cell biology.
在针对微生物感染的免疫反应中，CD8+ T 细胞会产生寿命短暂的效应细胞和记忆细胞，为机体提供持续的保护。尽管调节 CD8+ T 细胞分化的转录程序已经得到了广泛的研究，但长链非编码 RNA（lncRNA）在这一过程中的作用仍知之甚少。通过功能遗传敲低筛选，我们发现 lncRNA Malat1 是终末效应细胞和终末效应记忆（t-TEM）循环记忆亚群的调节因子。对染色质富集的 lncRNA 的评估表明，Malat1 与转录 lncRNA 聚集在一起，这些转录 lncRNA 在基因启动子和基因体中表现出增加的 RNA 相互作用。此外，我们观察到 Malat1 通过与 Ezh2 的直接相互作用，与许多与记忆细胞相关的基因中 H3K27me3 沉积的增加相关，从而促进终末效应细胞和 t-TEM 细胞的分化。我们的研究结果表明，Malat1 在调节 CD8+ T 细胞分化方面具有重要的功能作用，并拓宽了 lncRNA 在 CD8+ T 细胞生物学中的知识库。
