Widespread Shortening of 3' Untranslated Regions and Increased Exon Inclusion Are Evolutionarily Conserved Features of Innate Immune Responses to Infection.
The contribution of pre-mRNA processing mechanisms to the regulation of immune responses remains poorly studied despite emerging examples of their role as regulators of immune defenses. We sought to investigate the role of mRNA processing in the cellular responses of human macrophages to live bacterial infections. Here, we used mRNA sequencing to quantify gene expression and isoform abundances in primary macrophages from 60 individuals, before and after infection with Listeria monocytogenes and Salmonella typhimurium. In response to both bacteria we identified thousands of genes that significantly change isoform usage in response to infection, characterized by an overall increase in isoform diversity after infection. In response to both bacteria, we found global shifts towards (i) the inclusion of cassette exons and (ii) shorter 3' UTRs, with near-universal shifts towards usage of more upstream polyadenylation sites. Using complementary data collected in non-human primates, we show that these features are evolutionarily conserved among primates. Following infection, we identify candidate RNA processing factors whose expression is associated with individual-specific variation in isoform abundance. Finally, by profiling microRNA levels, we show that 3' UTRs with reduced abundance after infection are significantly enriched for target sites for particular miRNAs. These results suggest that the pervasive usage of shorter 3' UTRs is a mechanism for particular genes to evade repression by immune-activated miRNAs. Collectively, our results suggest that dynamic changes in RNA processing may play key roles in the regulation of innate immune responses.
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
Athma A
http://orcid.org/0000-0002-7995-9948
AA
Pai
Department of Biochemistry, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada.|Sainte-Justine Hospital Research Centre, Montreal, QC, Canada.
Golshid
G
Baharian
Sainte-Justine Hospital Research Centre, Montreal, QC, Canada.
Ariane
A
Pagé Sabourin
Sainte-Justine Hospital Research Centre, Montreal, QC, Canada.|Department of Pediatrics, Faculty of Medicine, University of Montreal, Montreal, QC, Canada.|Department of Anthropology, University of Illinois, Urbana-Champaign, IL, USA.
Jessica F
http://orcid.org/0000-0002-9087-3328
JF
Brinkworth
Department of Biochemistry, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada.|Sainte-Justine Hospital Research Centre, Montreal, QC, Canada.
Yohann
Y
Nédélec
Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
Joseph W
http://orcid.org/0000-0002-1579-5286
JW
Foley
Sainte-Justine Hospital Research Centre, Montreal, QC, Canada.
Jean-Christophe
http://orcid.org/0000-0001-7937-5160
JC
Grenier
Department of Organismic and Evolutionary Biology, FAS Center for Systems Biology, Harvard University, Cambridge, MA, USA.
Katherine J
http://orcid.org/0000-0002-1799-7295
KJ
Siddle
Sainte-Justine Hospital Research Centre, Montreal, QC, Canada.
Anne
A
Dumaine
Sainte-Justine Hospital Research Centre, Montreal, QC, Canada.
Vania
V
Yotova
Yerkes National Primate Research Center, Emory University, Atlanta, GA 30322, USA.|Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
Zachary P
ZP
Johnson
Texas Biomedical Research Institute, Southwest National Primate Research Center, San Antonio, TX, USA.
Robert E
RE
Lanford
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.|Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
Christopher B
CB
Burge
Sainte-Justine Hospital Research Centre, Montreal, QC, Canada.|Department of Pediatrics, Faculty of Medicine, University of Montreal, Montreal, QC, Canada.
Luis B
http://orcid.org/0000-0001-9456-367X
LB
Barreiro
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