Identification and analysis of long non-coding RNAs related to viral infection and antiviral response
In the last years, it has been stablished that the cell transcribes for many long non-coding RNAs (lncRNAs). It has been demonstrated that lncRNAs are deregulated in response to changes in cell status and that some lncRNAs act as key regulators of cell proliferation, development or cell homeostasis....
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| Format: | info:eu-repo/semantics/doctoralThesis |
| Language: | eng |
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2018
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| Subjects: | |
| Online Access: | https://hdl.handle.net/10171/50968 |
| _version_ | 1793400482864037888 |
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| author | Barriocanal, M. (Marina) Fortes, P. (Puri) |
| author_facet | Barriocanal, M. (Marina) Fortes, P. (Puri) |
| author_sort | Barriocanal, M. (Marina) |
| collection | DSpace |
| description | In the last years, it has been stablished that the cell transcribes for many long non-coding RNAs (lncRNAs). It has been demonstrated that lncRNAs are deregulated in response to changes in cell status and that some lncRNAs act as key regulators of cell proliferation, development or cell homeostasis. However, the function of most lncRNAs is still unknown, and little is known about lncRNAs related to infection and immune response. The aim of this work was to identify and analyze lncRNAs involved in the antiviral cellular response.
In the laboratory, they had performed transcriptome studies of control cells, cells infected with Hepatitis C virus (HCV) and/or cells treated with IFN-alpha by microarray and RNA sequencing. They found that IFN-alpha-treatment and/or HCV infection alters the levels of several lncRNAs. This PhD thesis describes the analysis of some of these lncRNAs.
Some of the IFN stimulated RNAs (ISRs) ISR2, ISR8 and ISR12, as well as, lncISG15 and lncBST2/BISPR are located in the genome close to well-known IFN stimulated genes (ISGs): GBP cluster, IRF1, IL6, ISG15 and BST2 respectively. This suggests that these lncRNAs might function by regulating the expression of their closer gene. Indeed, BISPR induces the expression of BST2 coding gene.
In addition, ISR8 seems to be a key enhancer for certain ISGs and pro-inflammatory genes. Indeed, ISR8 region presents enhancer marks, and disruption of this locus leads to stable cell lines that do not express ISR8 and are unable to induce several ISGs in response to IFN-alpha and/or NF-kB, although they have functional IFN and NF-kB pathways. Surprisingly, the phenotype observed in ISR8-disrupted cells is not rescued by exogenous expression of ISR8 or IRF1 or by decreasing chromatin repressors such as histone deacetylases or DNA methyltransferases to activate gene transcription.
Finally, HCV infection induces the expression of many oncogenic lncRNAs. This suggests that the increased rate of liver tumors observed in HCV-infected patients could, in part, result from increased expression of oncogenic lncRNAs. EGOT is a lncRNA induced by the cellular antiviral response and by infection with HCV in patients and cultured cells. EGOT is induced by NF-kB after RIG-I and PKR sensors activation by HCV genome. EGOT inhibition by gapmers leads to higher expression of several ISGs and decreased HCV titer, RNA and protein levels. Therefore, EGOT may function as a negative regulator of the antiviral pathway. |
| format | info:eu-repo/semantics/doctoralThesis |
| id | oai:dadun.unav.edu:10171-50968 |
| institution | Universidad de Navarra |
| language | eng |
| publishDate | 2018 |
| record_format | dspace |
| spelling | oai:dadun.unav.edu:10171-509682020-07-21T01:12:39Z Identification and analysis of long non-coding RNAs related to viral infection and antiviral response Barriocanal, M. (Marina) Fortes, P. (Puri) viral infection antiviral response Materias Investigacion::Ciencias de la Salud::Genética In the last years, it has been stablished that the cell transcribes for many long non-coding RNAs (lncRNAs). It has been demonstrated that lncRNAs are deregulated in response to changes in cell status and that some lncRNAs act as key regulators of cell proliferation, development or cell homeostasis. However, the function of most lncRNAs is still unknown, and little is known about lncRNAs related to infection and immune response. The aim of this work was to identify and analyze lncRNAs involved in the antiviral cellular response. In the laboratory, they had performed transcriptome studies of control cells, cells infected with Hepatitis C virus (HCV) and/or cells treated with IFN-alpha by microarray and RNA sequencing. They found that IFN-alpha-treatment and/or HCV infection alters the levels of several lncRNAs. This PhD thesis describes the analysis of some of these lncRNAs. Some of the IFN stimulated RNAs (ISRs) ISR2, ISR8 and ISR12, as well as, lncISG15 and lncBST2/BISPR are located in the genome close to well-known IFN stimulated genes (ISGs): GBP cluster, IRF1, IL6, ISG15 and BST2 respectively. This suggests that these lncRNAs might function by regulating the expression of their closer gene. Indeed, BISPR induces the expression of BST2 coding gene. In addition, ISR8 seems to be a key enhancer for certain ISGs and pro-inflammatory genes. Indeed, ISR8 region presents enhancer marks, and disruption of this locus leads to stable cell lines that do not express ISR8 and are unable to induce several ISGs in response to IFN-alpha and/or NF-kB, although they have functional IFN and NF-kB pathways. Surprisingly, the phenotype observed in ISR8-disrupted cells is not rescued by exogenous expression of ISR8 or IRF1 or by decreasing chromatin repressors such as histone deacetylases or DNA methyltransferases to activate gene transcription. Finally, HCV infection induces the expression of many oncogenic lncRNAs. This suggests that the increased rate of liver tumors observed in HCV-infected patients could, in part, result from increased expression of oncogenic lncRNAs. EGOT is a lncRNA induced by the cellular antiviral response and by infection with HCV in patients and cultured cells. EGOT is induced by NF-kB after RIG-I and PKR sensors activation by HCV genome. EGOT inhibition by gapmers leads to higher expression of several ISGs and decreased HCV titer, RNA and protein levels. Therefore, EGOT may function as a negative regulator of the antiviral pathway. 2018-04-12T08:05:16Z 2018-04-12T08:05:16Z 2018-04-12 2017-12-14 info:eu-repo/semantics/doctoralThesis https://hdl.handle.net/10171/50968 eng info:eu-repo/semantics/openAccess application/pdf |
| spellingShingle | viral infection antiviral response Materias Investigacion::Ciencias de la Salud::Genética Barriocanal, M. (Marina) Fortes, P. (Puri) Identification and analysis of long non-coding RNAs related to viral infection and antiviral response |
| title | Identification and analysis of long non-coding RNAs related to viral infection and antiviral response |
| title_full | Identification and analysis of long non-coding RNAs related to viral infection and antiviral response |
| title_fullStr | Identification and analysis of long non-coding RNAs related to viral infection and antiviral response |
| title_full_unstemmed | Identification and analysis of long non-coding RNAs related to viral infection and antiviral response |
| title_short | Identification and analysis of long non-coding RNAs related to viral infection and antiviral response |
| title_sort | identification and analysis of long non-coding rnas related to viral infection and antiviral response |
| topic | viral infection antiviral response Materias Investigacion::Ciencias de la Salud::Genética |
| url | https://hdl.handle.net/10171/50968 |
| work_keys_str_mv | AT barriocanalmmarina identificationandanalysisoflongnoncodingrnasrelatedtoviralinfectionandantiviralresponse AT fortesppuri identificationandanalysisoflongnoncodingrnasrelatedtoviralinfectionandantiviralresponse |