Widespread Shortening of 3′ Untranslated Regions and Increased Exon Inclusion Are Evolutionarily Conserved Features of Innate Immune Responses to Infection

被引：73

作者：

Pai, Athma A. ^{[1
]}

Baharian, Golshid ^{[2
,3
]}

Sabourin, Ariane Page ^{[3
]}

Brinkworth, Jessica F. ^{[3
,4
,5
]}

Nedelec, Yohann ^{[2
,3
]}

Foley, Joseph W. ^{[6
]}

Grenier, Jean-Christophe ^{[3
]}

Siddle, Katherine J. ^{[7
]}

Dumaine, Anne ^{[3
]}

Yotova, Vania ^{[3
]}

Johnson, Zachary P. ^{[8
,9
]}

Lanford, Robert E. ^{[10
]}

Burge, Christopher B. ^{[1
,11
]}

Barreiro, Luis B. ^{[3
,4
]}

机构：

[1] MIT, Dept Biol, Cambridge, MA 02139 USA

[2] Univ Montreal, Fac Med, Dept Biochem, Montreal, PQ, Canada

[3] Hop St Justine, Res Ctr, Montreal, PQ, Canada

[4] Univ Montreal, Fac Med, Dept Pediat, Montreal, PQ, Canada

[5] Univ Illinois, Dept Anthropol, 109 Davenport Hall, Urbana, IL 61801 USA

[6] Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA

[7] Harvard Univ, Dept Organism & Evolutionary Biol, FAS Ctr Syst Biol, Cambridge, MA 02138 USA

[8] Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30322 USA

[9] Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA 30322 USA

[10] Southwest Natl Primate Res Ctr, Texas Biomed Res Inst, San Antonio, TX USA

[11] MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA

来源：

PLOS GENETICS | 2016年 / 12卷 / 09期

基金：

加拿大自然科学与工程研究理事会; 加拿大健康研究院; 美国国家科学基金会;

关键词：

MESSENGER-RNA DECAY; ALTERNATIVE POLYADENYLATION; SPLICE VARIANT; SR PROTEIN; EXPRESSION; ISOFORM; IDENTIFICATION; RECEPTORS; TRANSCRIPTION; CONSEQUENCES;

D O I：

10.1371/journal.pgen.1006338

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页数：24