Limits...
Unique signatures of long noncoding RNA expression in response to virus infection and altered innate immune signaling.

Peng X, Gralinski L, Armour CD, Ferris MT, Thomas MJ, Proll S, Bradel-Tretheway BG, Korth MJ, Castle JC, Biery MC, Bouzek HK, Haynor DR, Frieman MB, Heise M, Raymond CK, Baric RS, Katze MG - MBio (2010)

Bottom Line: Studies of the host response to virus infection typically focus on protein-coding genes.Using next-generation sequencing, we performed a whole-transcriptome analysis of the host response to severe acute respiratory syndrome coronavirus (SARS-CoV) infection across four founder mouse strains of the Collaborative Cross.Moreover, studies of a subset of these ncRNAs and genomic regions showed the following. (i) Most were similarly regulated in response to influenza virus infection. (ii) They had distinctive kinetic expression profiles in type I interferon receptor and STAT1 knockout mice during SARS-CoV infection, including unique signatures of ncRNA expression associated with lethal infection. (iii) Over 40% were similarly regulated in vitro in response to both influenza virus infection and interferon treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington, USA.

ABSTRACT
Studies of the host response to virus infection typically focus on protein-coding genes. However, non-protein-coding RNAs (ncRNAs) are transcribed in mammalian cells, and the roles of many of these ncRNAs remain enigmas. Using next-generation sequencing, we performed a whole-transcriptome analysis of the host response to severe acute respiratory syndrome coronavirus (SARS-CoV) infection across four founder mouse strains of the Collaborative Cross. We observed differential expression of approximately 500 annotated, long ncRNAs and 1,000 nonannotated genomic regions during infection. Moreover, studies of a subset of these ncRNAs and genomic regions showed the following. (i) Most were similarly regulated in response to influenza virus infection. (ii) They had distinctive kinetic expression profiles in type I interferon receptor and STAT1 knockout mice during SARS-CoV infection, including unique signatures of ncRNA expression associated with lethal infection. (iii) Over 40% were similarly regulated in vitro in response to both influenza virus infection and interferon treatment. These findings represent the first discovery of the widespread differential expression of long ncRNAs in response to virus infection and suggest that ncRNAs are involved in regulating the host response, including innate immunity. At the same time, virus infection models provide a unique platform for studying the biology and regulation of ncRNAs.

Show MeSH

Related in: MedlinePlus

Differential expression of 509 annotated ncRNAs and corresponding neighbor protein-coding genes. (a) Heat maps of the infected/mock-infected expression ratios (log2 scale) of 509 annotated ncRNAs and their corresponding neighbor protein-coding genes in four mouse strains. The blue bands on the left indicate those ncRNAs overlapping with long intergenic noncoding RNAs as reported in reference 7. On the heat map, red indicates upregulation during infection, while green indicates downregulation during infection. Below the heat map for neighbor protein-coding genes, “not detected” indicates protein-coding genes with less than 20 uniquely mapped reads in all samples. (b) Functional annotation of protein-coding genes neighboring differentially expressed ncRNAs as shown in panel a. The annotation terms in the most significant functional annotation cluster identified by using the DAVID functional annotation tool are shown, and plotted as the –log10P value for the enrichment of each annotation term.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2962437&req=5

f6: Differential expression of 509 annotated ncRNAs and corresponding neighbor protein-coding genes. (a) Heat maps of the infected/mock-infected expression ratios (log2 scale) of 509 annotated ncRNAs and their corresponding neighbor protein-coding genes in four mouse strains. The blue bands on the left indicate those ncRNAs overlapping with long intergenic noncoding RNAs as reported in reference 7. On the heat map, red indicates upregulation during infection, while green indicates downregulation during infection. Below the heat map for neighbor protein-coding genes, “not detected” indicates protein-coding genes with less than 20 uniquely mapped reads in all samples. (b) Functional annotation of protein-coding genes neighboring differentially expressed ncRNAs as shown in panel a. The annotation terms in the most significant functional annotation cluster identified by using the DAVID functional annotation tool are shown, and plotted as the –log10P value for the enrichment of each annotation term.

Mentions: Another approach for inferring putative functions of long ncRNAs is to examine protein-coding genes located near ncRNAs of interest (7, 10). For each mouse strain, we examined the infection-induced patterns of expression of ncRNAs and their paired neighbor protein-coding genes (see the supplementary material). Interestingly, we found that the changes in expression of neighbor protein-coding genes (fold changes) were significantly associated with the fold changes in expression of the corresponding ncRNAs during infection (P values =1.8e−22 to 2.4e−32, analysis of variance [ANOVA] F test, Fig. 6a, and the supplementary material). We utilized the DAVID Functional Annotation Tool (11) for functional enrichment analysis on those neighbor protein-coding genes. The most significant functional group identified using DAVID consisted of 11 similar annotation terms related to gene expression (Fig. 6b). Interestingly, previous studies also reported that the genes in neighboring long ncRNAs exhibit a bias toward transcription-related factors (7, 10). We therefore hypothesize that long ncRNAs might also be able to modulate host responses through neighboring protein-coding genes.


Unique signatures of long noncoding RNA expression in response to virus infection and altered innate immune signaling.

Peng X, Gralinski L, Armour CD, Ferris MT, Thomas MJ, Proll S, Bradel-Tretheway BG, Korth MJ, Castle JC, Biery MC, Bouzek HK, Haynor DR, Frieman MB, Heise M, Raymond CK, Baric RS, Katze MG - MBio (2010)

Differential expression of 509 annotated ncRNAs and corresponding neighbor protein-coding genes. (a) Heat maps of the infected/mock-infected expression ratios (log2 scale) of 509 annotated ncRNAs and their corresponding neighbor protein-coding genes in four mouse strains. The blue bands on the left indicate those ncRNAs overlapping with long intergenic noncoding RNAs as reported in reference 7. On the heat map, red indicates upregulation during infection, while green indicates downregulation during infection. Below the heat map for neighbor protein-coding genes, “not detected” indicates protein-coding genes with less than 20 uniquely mapped reads in all samples. (b) Functional annotation of protein-coding genes neighboring differentially expressed ncRNAs as shown in panel a. The annotation terms in the most significant functional annotation cluster identified by using the DAVID functional annotation tool are shown, and plotted as the –log10P value for the enrichment of each annotation term.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2962437&req=5

f6: Differential expression of 509 annotated ncRNAs and corresponding neighbor protein-coding genes. (a) Heat maps of the infected/mock-infected expression ratios (log2 scale) of 509 annotated ncRNAs and their corresponding neighbor protein-coding genes in four mouse strains. The blue bands on the left indicate those ncRNAs overlapping with long intergenic noncoding RNAs as reported in reference 7. On the heat map, red indicates upregulation during infection, while green indicates downregulation during infection. Below the heat map for neighbor protein-coding genes, “not detected” indicates protein-coding genes with less than 20 uniquely mapped reads in all samples. (b) Functional annotation of protein-coding genes neighboring differentially expressed ncRNAs as shown in panel a. The annotation terms in the most significant functional annotation cluster identified by using the DAVID functional annotation tool are shown, and plotted as the –log10P value for the enrichment of each annotation term.
Mentions: Another approach for inferring putative functions of long ncRNAs is to examine protein-coding genes located near ncRNAs of interest (7, 10). For each mouse strain, we examined the infection-induced patterns of expression of ncRNAs and their paired neighbor protein-coding genes (see the supplementary material). Interestingly, we found that the changes in expression of neighbor protein-coding genes (fold changes) were significantly associated with the fold changes in expression of the corresponding ncRNAs during infection (P values =1.8e−22 to 2.4e−32, analysis of variance [ANOVA] F test, Fig. 6a, and the supplementary material). We utilized the DAVID Functional Annotation Tool (11) for functional enrichment analysis on those neighbor protein-coding genes. The most significant functional group identified using DAVID consisted of 11 similar annotation terms related to gene expression (Fig. 6b). Interestingly, previous studies also reported that the genes in neighboring long ncRNAs exhibit a bias toward transcription-related factors (7, 10). We therefore hypothesize that long ncRNAs might also be able to modulate host responses through neighboring protein-coding genes.

Bottom Line: Studies of the host response to virus infection typically focus on protein-coding genes.Using next-generation sequencing, we performed a whole-transcriptome analysis of the host response to severe acute respiratory syndrome coronavirus (SARS-CoV) infection across four founder mouse strains of the Collaborative Cross.Moreover, studies of a subset of these ncRNAs and genomic regions showed the following. (i) Most were similarly regulated in response to influenza virus infection. (ii) They had distinctive kinetic expression profiles in type I interferon receptor and STAT1 knockout mice during SARS-CoV infection, including unique signatures of ncRNA expression associated with lethal infection. (iii) Over 40% were similarly regulated in vitro in response to both influenza virus infection and interferon treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington, USA.

ABSTRACT
Studies of the host response to virus infection typically focus on protein-coding genes. However, non-protein-coding RNAs (ncRNAs) are transcribed in mammalian cells, and the roles of many of these ncRNAs remain enigmas. Using next-generation sequencing, we performed a whole-transcriptome analysis of the host response to severe acute respiratory syndrome coronavirus (SARS-CoV) infection across four founder mouse strains of the Collaborative Cross. We observed differential expression of approximately 500 annotated, long ncRNAs and 1,000 nonannotated genomic regions during infection. Moreover, studies of a subset of these ncRNAs and genomic regions showed the following. (i) Most were similarly regulated in response to influenza virus infection. (ii) They had distinctive kinetic expression profiles in type I interferon receptor and STAT1 knockout mice during SARS-CoV infection, including unique signatures of ncRNA expression associated with lethal infection. (iii) Over 40% were similarly regulated in vitro in response to both influenza virus infection and interferon treatment. These findings represent the first discovery of the widespread differential expression of long ncRNAs in response to virus infection and suggest that ncRNAs are involved in regulating the host response, including innate immunity. At the same time, virus infection models provide a unique platform for studying the biology and regulation of ncRNAs.

Show MeSH
Related in: MedlinePlus