Atianand Maninjay K, Hu Wenqian, Satpathy Ansuman T, Shen Ying, Ricci Emiliano P, Alvarez-Dominguez Juan R, Bhatta Ankit, Schattgen Stefan A, McGowan Jason D, Blin Juliana, Braun Joerg E, Gandhi Pallavi, Moore Melissa J, Chang Howard Y, Lodish Harvey F, Caffrey Daniel R, Fitzgerald Katherine A
Program in Innate Immunity, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Whitehead Institute, Massachusetts Institute of Technology (MIT), Cambridge, MA 02142, USA.
Cell. 2016 Jun 16;165(7):1672-1685. doi: 10.1016/j.cell.2016.05.075.
Long intergenic noncoding RNAs (lincRNAs) are important regulators of gene expression. Although lincRNAs are expressed in immune cells, their functions in immunity are largely unexplored. Here, we identify an immunoregulatory lincRNA, lincRNA-EPS, that is precisely regulated in macrophages to control the expression of immune response genes (IRGs). Transcriptome analysis of macrophages from lincRNA-EPS-deficient mice, combined with gain-of-function and rescue experiments, revealed a specific role for this lincRNA in restraining IRG expression. Consistently, lincRNA-EPS-deficient mice manifest enhanced inflammation and lethality following endotoxin challenge in vivo. lincRNA-EPS localizes at regulatory regions of IRGs to control nucleosome positioning and repress transcription. Further, lincRNA-EPS mediates these effects by interacting with heterogeneous nuclear ribonucleoprotein L via a CANACA motif located in its 3' end. Together, these findings identify lincRNA-EPS as a repressor of inflammatory responses, highlighting the importance of lincRNAs in the immune system.
长链基因间非编码RNA（lincRNA）是基因表达的重要调节因子。尽管lincRNA在免疫细胞中表达，但其在免疫中的功能在很大程度上尚未被探索。在此，我们鉴定出一种免疫调节性lincRNA，即lincRNA-EPS，它在巨噬细胞中受到精确调控，以控制免疫反应基因（IRG）的表达。对来自lincRNA-EPS缺陷小鼠的巨噬细胞进行转录组分析，并结合功能获得和拯救实验，揭示了这种lincRNA在抑制IRG表达中的特定作用。一致地，lincRNA-EPS缺陷小鼠在体内受到内毒素攻击后表现出炎症增强和致死率增加。lincRNA-EPS定位于IRG的调控区域，以控制核小体定位并抑制转录。此外，lincRNA-EPS通过位于其3'端的CANACA基序与不均一核核糖核蛋白L相互作用来介导这些效应。总之，这些发现确定lincRNA-EPS是炎症反应的抑制因子，突出了lincRNA在免疫系统中的重要性。
