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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

ISRs respond to viral infections in vivo. Expression levels of ISR2 (A and B), ISR8 (A), ISR12 (A), and GBP1 (B) were evaluated in livers from HCV-negative (n = 19) to HCV-positive (n = 13) patients (A) and in blood cells (B) isolated from healthy patients (n = 14) or from patients infected with HIV (n = 7). Statistical significance was calculated using a two-tailed non-parametric Mann–Whitneyt-test.
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Figure 9: ISRs respond to viral infections in vivo. Expression levels of ISR2 (A and B), ISR8 (A), ISR12 (A), and GBP1 (B) were evaluated in livers from HCV-negative (n = 19) to HCV-positive (n = 13) patients (A) and in blood cells (B) isolated from healthy patients (n = 14) or from patients infected with HIV (n = 7). Statistical significance was calculated using a two-tailed non-parametric Mann–Whitneyt-test.

Mentions: We were surprised to see that the strongest increase in ISR2 and 8 was observed in cells infected with HCV, an IFN-sensitive virus that employs several viral proteins to block the IFN pathway. Increased expression was also observed for GBP1 and IRF1 but not for other ISGs such as OAS (Figure 8 and data not shown). To determine whether a similar upregulation could be observed in HCV patients, levels of ISR2, 8, and 12 were evaluated in livers from HCV-negative (n = 19) to HCV-positive (n = 13) patients. The results show that both ISR2 and 8 are significantly upregulated in HCV patients (Figure 9A). No differences were observed in the levels of ISR12 in the same samples. Finally, we wanted to determine whether these lncRNAs also respond to other chronic viral infections relevant for human health. Therefore, we evaluated the expression of ISR2, 8, and 12 in blood cells isolated from healthy patients or from patients chronically infected with HIV. We could not detect expression of ISR8 or 12 in these samples. However, both ISR2 and GBP1 were significantly upregulated in HIV-infected patient cells (Figure 9B).


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)

ISRs respond to viral infections in vivo. Expression levels of ISR2 (A and B), ISR8 (A), ISR12 (A), and GBP1 (B) were evaluated in livers from HCV-negative (n = 19) to HCV-positive (n = 13) patients (A) and in blood cells (B) isolated from healthy patients (n = 14) or from patients infected with HIV (n = 7). Statistical significance was calculated using a two-tailed non-parametric Mann–Whitneyt-test.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 9: ISRs respond to viral infections in vivo. Expression levels of ISR2 (A and B), ISR8 (A), ISR12 (A), and GBP1 (B) were evaluated in livers from HCV-negative (n = 19) to HCV-positive (n = 13) patients (A) and in blood cells (B) isolated from healthy patients (n = 14) or from patients infected with HIV (n = 7). Statistical significance was calculated using a two-tailed non-parametric Mann–Whitneyt-test.
Mentions: We were surprised to see that the strongest increase in ISR2 and 8 was observed in cells infected with HCV, an IFN-sensitive virus that employs several viral proteins to block the IFN pathway. Increased expression was also observed for GBP1 and IRF1 but not for other ISGs such as OAS (Figure 8 and data not shown). To determine whether a similar upregulation could be observed in HCV patients, levels of ISR2, 8, and 12 were evaluated in livers from HCV-negative (n = 19) to HCV-positive (n = 13) patients. The results show that both ISR2 and 8 are significantly upregulated in HCV patients (Figure 9A). No differences were observed in the levels of ISR12 in the same samples. Finally, we wanted to determine whether these lncRNAs also respond to other chronic viral infections relevant for human health. Therefore, we evaluated the expression of ISR2, 8, and 12 in blood cells isolated from healthy patients or from patients chronically infected with HIV. We could not detect expression of ISR8 or 12 in these samples. However, both ISR2 and GBP1 were significantly upregulated in HIV-infected patient cells (Figure 9B).

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