A Long Noncoding RNA lincRNA-EPS Acts as a Transcriptional Brake to Restrain Inflammation.
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.
Program in Innate Immunity, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Maninjay K
MK
Atianand
Whitehead Institute, Massachusetts Institute of Technology (MIT), Cambridge, MA 02142, USA.
Wenqian
W
Hu
Center for Personal Dynamic Regulomes and Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Ansuman T
AT
Satpathy
Center for Personal Dynamic Regulomes and Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Ying
Y
Shen
Howard Hughes Medical Institute and Department of Biochemistry and Pharmacology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Emiliano P
EP
Ricci
Whitehead Institute, Massachusetts Institute of Technology (MIT), Cambridge, MA 02142, USA.
Juan R
JR
Alvarez-Dominguez
Program in Innate Immunity, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Ankit
A
Bhatta
Program in Innate Immunity, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Stefan A
SA
Schattgen
Program in Innate Immunity, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Jason D
JD
McGowan
Program in Innate Immunity, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Juliana
J
Blin
Howard Hughes Medical Institute and Department of Biochemistry and Pharmacology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Joerg E
JE
Braun
Program in Innate Immunity, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Pallavi
P
Gandhi
Howard Hughes Medical Institute and Department of Biochemistry and Pharmacology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Melissa J
MJ
Moore
Center for Personal Dynamic Regulomes and Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Howard Y
HY
Chang
Whitehead Institute, Massachusetts Institute of Technology (MIT), Cambridge, MA 02142, USA.
Harvey F
HF
Lodish
Program in Innate Immunity, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Daniel R
DR
Caffrey
Program in Innate Immunity, University of Massachusetts Medical School, Worcester, MA 01605, USA; Centre for Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, NTNU, 7491 Trondheim, Norway. Electronic address: kate.fitzgerald@umassmed.edu.
Katherine A
KA
Fitzgerald
D000818:Animals; D002842:Chromatids / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D008089:Listeria monocytogenes / Q000502:physiology; D008088:Listeriosis / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*; D010253:Respirovirus Infections / Q000276:immunology; D029082:Sendai virus / Q000502:physiology; D051193:Toll-Like Receptors / Q000378:metabolism; D059467:Transcriptome
C000611824:EPS long non-coding RNA, mouse; D062085:RNA, Long Noncoding; D051193:Toll-Like Receptors