Limits...
Type I Interferon Regulates the Expression of Long Non-Coding RNAs.

Carnero E, Barriocanal M, Segura V, Guruceaga E, Prior C, Börner K, Grimm D, Fortes P - Front Immunol (2014)

Bottom Line: Surprisingly, both ISR2 and 8 were significantly upregulated in cultured cells and livers from patients infected with HCV.This is relevant as genome-wide guilt-by-association studies predict that ISR2, 8, and 12 may function in viral processes, in the IFN pathway and the antiviral response.Therefore, we propose that these lncRNAs could be induced by IFN to function as positive or negative regulators of the antiviral response.

View Article: PubMed Central - PubMed

Affiliation: Department of Gene therapy and Hepatology, Center for Applied Medical Research (CIMA), University of Navarra , Pamplona , Spain.

ABSTRACT
Interferons (IFNs) are key players in the antiviral response. IFN sensing by the cell activates transcription of IFN-stimulated genes (ISGs) able to induce an antiviral state by affecting viral replication and release. IFN also induces the expression of ISGs that function as negative regulators to limit the strength and duration of IFN response. The ISGs identified so far belong to coding genes. However, only a small proportion of the transcriptome corresponds to coding transcripts and it has been estimated that there could be as many coding as long non-coding RNAs (lncRNAs). To address whether IFN can also regulate the expression of lncRNAs, we analyzed the transcriptome of HuH7 cells treated or not with IFNα2 by expression arrays. Analysis of the arrays showed increased levels of several well-characterized coding genes that respond to IFN both at early or late times. Furthermore, we identified several IFN-stimulated or -downregulated lncRNAs (ISRs and IDRs). Further validation showed that ISR2, 8, and 12 expression mimics that of their neighboring genes GBP1, IRF1, and IL6, respectively, all related to the IFN response. These genes are induced in response to different doses of IFNα2 in different cell lines at early (ISR2 or 8) or later (ISR12) time points. IFNβ also induced the expression of these lncRNAs. ISR2 and 8 were also induced by an influenza virus unable to block the IFN response but not by other wild-type lytic viruses tested. Surprisingly, both ISR2 and 8 were significantly upregulated in cultured cells and livers from patients infected with HCV. Increased levels of ISR2 were also detected in patients chronically infected with HIV. This is relevant as genome-wide guilt-by-association studies predict that ISR2, 8, and 12 may function in viral processes, in the IFN pathway and the antiviral response. Therefore, we propose that these lncRNAs could be induced by IFN to function as positive or negative regulators of the antiviral response.

No MeSH data available.


Related in: MedlinePlus

Correlation of expression between ISR2, 8, and 12 and their coding partners, and guilt-by-association analysis. (A) Expression levels observed for ISR2, 8, and 12 in Figures 4A and 5 were compared to the expression levels of their coding neighbors GBP1, IRF1, and IL6, respectively, in Figures 1 and 4C. A correlation analysis was performed and statistical significance was calculated using a two-tailed non-parametric Spearman analysis. (B) Clustering of the guilt-by-association results showing significant GO terms. The z-score color scale is shown at the bottom of the image.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4222131&req=5

Figure 7: Correlation of expression between ISR2, 8, and 12 and their coding partners, and guilt-by-association analysis. (A) Expression levels observed for ISR2, 8, and 12 in Figures 4A and 5 were compared to the expression levels of their coding neighbors GBP1, IRF1, and IL6, respectively, in Figures 1 and 4C. A correlation analysis was performed and statistical significance was calculated using a two-tailed non-parametric Spearman analysis. (B) Clustering of the guilt-by-association results showing significant GO terms. The z-score color scale is shown at the bottom of the image.

Mentions: As indicated above, each ISR and its neighboring coding gene have similar induction patterns in response to IFN (compare Figure 1 and Figure 5 or Figures 4A,C). This suggests that they could be co-regulated and therefore, that they could share similar functions. To analyze in more detail whether the expression level of each ISR correlates significantly with the expression level of its neighboring coding gene, we performed correlation studies. We compared the levels of each coding/non-coding pair in all the samples evaluated in Figures 1, 4, and 5. The results show a highly significant positive correlation between ISR2 and GBP1 or ISR8 and IRF1. In contrast, ISR12 had a non-significant correlation with IL6 (Figure 7A). Expression of neither ISR2 nor ISR8 significantly correlated with the expression of other ISGs such as OAS or BST2 (data not shown).


Type I Interferon Regulates the Expression of Long Non-Coding RNAs.

Carnero E, Barriocanal M, Segura V, Guruceaga E, Prior C, Börner K, Grimm D, Fortes P - Front Immunol (2014)

Correlation of expression between ISR2, 8, and 12 and their coding partners, and guilt-by-association analysis. (A) Expression levels observed for ISR2, 8, and 12 in Figures 4A and 5 were compared to the expression levels of their coding neighbors GBP1, IRF1, and IL6, respectively, in Figures 1 and 4C. A correlation analysis was performed and statistical significance was calculated using a two-tailed non-parametric Spearman analysis. (B) Clustering of the guilt-by-association results showing significant GO terms. The z-score color scale is shown at the bottom of the image.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4222131&req=5

Figure 7: Correlation of expression between ISR2, 8, and 12 and their coding partners, and guilt-by-association analysis. (A) Expression levels observed for ISR2, 8, and 12 in Figures 4A and 5 were compared to the expression levels of their coding neighbors GBP1, IRF1, and IL6, respectively, in Figures 1 and 4C. A correlation analysis was performed and statistical significance was calculated using a two-tailed non-parametric Spearman analysis. (B) Clustering of the guilt-by-association results showing significant GO terms. The z-score color scale is shown at the bottom of the image.
Mentions: As indicated above, each ISR and its neighboring coding gene have similar induction patterns in response to IFN (compare Figure 1 and Figure 5 or Figures 4A,C). This suggests that they could be co-regulated and therefore, that they could share similar functions. To analyze in more detail whether the expression level of each ISR correlates significantly with the expression level of its neighboring coding gene, we performed correlation studies. We compared the levels of each coding/non-coding pair in all the samples evaluated in Figures 1, 4, and 5. The results show a highly significant positive correlation between ISR2 and GBP1 or ISR8 and IRF1. In contrast, ISR12 had a non-significant correlation with IL6 (Figure 7A). Expression of neither ISR2 nor ISR8 significantly correlated with the expression of other ISGs such as OAS or BST2 (data not shown).

Bottom Line: Surprisingly, both ISR2 and 8 were significantly upregulated in cultured cells and livers from patients infected with HCV.This is relevant as genome-wide guilt-by-association studies predict that ISR2, 8, and 12 may function in viral processes, in the IFN pathway and the antiviral response.Therefore, we propose that these lncRNAs could be induced by IFN to function as positive or negative regulators of the antiviral response.

View Article: PubMed Central - PubMed

Affiliation: Department of Gene therapy and Hepatology, Center for Applied Medical Research (CIMA), University of Navarra , Pamplona , Spain.

ABSTRACT
Interferons (IFNs) are key players in the antiviral response. IFN sensing by the cell activates transcription of IFN-stimulated genes (ISGs) able to induce an antiviral state by affecting viral replication and release. IFN also induces the expression of ISGs that function as negative regulators to limit the strength and duration of IFN response. The ISGs identified so far belong to coding genes. However, only a small proportion of the transcriptome corresponds to coding transcripts and it has been estimated that there could be as many coding as long non-coding RNAs (lncRNAs). To address whether IFN can also regulate the expression of lncRNAs, we analyzed the transcriptome of HuH7 cells treated or not with IFNα2 by expression arrays. Analysis of the arrays showed increased levels of several well-characterized coding genes that respond to IFN both at early or late times. Furthermore, we identified several IFN-stimulated or -downregulated lncRNAs (ISRs and IDRs). Further validation showed that ISR2, 8, and 12 expression mimics that of their neighboring genes GBP1, IRF1, and IL6, respectively, all related to the IFN response. These genes are induced in response to different doses of IFNα2 in different cell lines at early (ISR2 or 8) or later (ISR12) time points. IFNβ also induced the expression of these lncRNAs. ISR2 and 8 were also induced by an influenza virus unable to block the IFN response but not by other wild-type lytic viruses tested. Surprisingly, both ISR2 and 8 were significantly upregulated in cultured cells and livers from patients infected with HCV. Increased levels of ISR2 were also detected in patients chronically infected with HIV. This is relevant as genome-wide guilt-by-association studies predict that ISR2, 8, and 12 may function in viral processes, in the IFN pathway and the antiviral response. Therefore, we propose that these lncRNAs could be induced by IFN to function as positive or negative regulators of the antiviral response.

No MeSH data available.


Related in: MedlinePlus