Murine Long Noncoding RNA Morrbid Contributes in the Regulation of NRAS Splicing in Hepatocytes In Vitro
The coupling of alternative splicing with the nonsense-mediated decay (NMD) pathway maintains quality control of the transcriptome in eukaryotes by eliminating transcripts with premature termination codons (PTC) and fine-tunes gene expression. Long noncoding RNA (lncRNA) can regulate multiple cellul...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-08-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/16/5605 |
| _version_ | 1797560210416467968 |
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| author | Anna Fefilova Pavel Melnikov Tatiana Prikazchikova Tatiana Abakumova Ilya Kurochkin Pavel V. Mazin Rustam Ziganshin Olga Sergeeva Timofei S. Zatsepin |
| author_facet | Anna Fefilova Pavel Melnikov Tatiana Prikazchikova Tatiana Abakumova Ilya Kurochkin Pavel V. Mazin Rustam Ziganshin Olga Sergeeva Timofei S. Zatsepin |
| author_sort | Anna Fefilova |
| collection | DOAJ |
| description | The coupling of alternative splicing with the nonsense-mediated decay (NMD) pathway maintains quality control of the transcriptome in eukaryotes by eliminating transcripts with premature termination codons (PTC) and fine-tunes gene expression. Long noncoding RNA (lncRNA) can regulate multiple cellular processes, including alternative splicing. Previously, murine Morrbid (myeloid RNA repressor of Bcl2l11 induced death) lncRNA was described as a locus-specific controller of the lifespan of short-living myeloid cells via transcription regulation of the apoptosis-related Bcl2l11 protein. Here, we report that murine Morrbid lncRNA in hepatocytes participates in the regulation of proto-oncogene NRAS (neuroblastoma RAS viral oncogene homolog) splicing, including the formation of the isoform with PTC. We observed a significant increase of the NRAS isoform with PTC in hepatocytes with depleted Morrbid lncRNA. We demonstrated that the NRAS isoform with PTC is degraded via the NMD pathway. This transcript is presented almost only in the nucleus and has a half-life ~four times lower than other NRAS transcripts. Additionally, in UPF1 knockdown hepatocytes (the key NMD factor), we observed a significant increase of the NRAS isoform with PTC. By a modified capture hybridization (CHART) analysis of the protein targets, we uncovered interactions of Morrbid lncRNA with the SFPQ (splicing factor proline and glutamine rich)-NONO (non-POU domain-containing octamer-binding protein) splicing complex. Finally, we propose the regulation mechanism of NRAS splicing in murine hepatocytes by alternative splicing coupled with the NMD pathway with the input of Morrbid lncRNA. |
| first_indexed | 2024-03-10T17:57:10Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T17:57:10Z |
| publishDate | 2020-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-99dfbec63d704bb7ad8f930d57cd5c042023-11-20T09:10:04ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-08-012116560510.3390/ijms21165605Murine Long Noncoding RNA Morrbid Contributes in the Regulation of NRAS Splicing in Hepatocytes In VitroAnna Fefilova0Pavel Melnikov1Tatiana Prikazchikova2Tatiana Abakumova3Ilya Kurochkin4Pavel V. Mazin5Rustam Ziganshin6Olga Sergeeva7Timofei S. Zatsepin8Center of Life Sciences, Skolkovo Institute of Science and Technology, 121205 Moscow, RussiaSerbsky National Medical Research Center for Psychiatry and Narcology, 119034 Moscow, RussiaCenter of Life Sciences, Skolkovo Institute of Science and Technology, 121205 Moscow, RussiaCenter of Life Sciences, Skolkovo Institute of Science and Technology, 121205 Moscow, RussiaCenter of Life Sciences, Skolkovo Institute of Science and Technology, 121205 Moscow, RussiaCenter of Life Sciences, Skolkovo Institute of Science and Technology, 121205 Moscow, RussiaShemyakin-Ovchinnikov Institute of Bioorganic Chemistry, 117997 Moscow, RussiaCenter of Life Sciences, Skolkovo Institute of Science and Technology, 121205 Moscow, RussiaCenter of Life Sciences, Skolkovo Institute of Science and Technology, 121205 Moscow, RussiaThe coupling of alternative splicing with the nonsense-mediated decay (NMD) pathway maintains quality control of the transcriptome in eukaryotes by eliminating transcripts with premature termination codons (PTC) and fine-tunes gene expression. Long noncoding RNA (lncRNA) can regulate multiple cellular processes, including alternative splicing. Previously, murine Morrbid (myeloid RNA repressor of Bcl2l11 induced death) lncRNA was described as a locus-specific controller of the lifespan of short-living myeloid cells via transcription regulation of the apoptosis-related Bcl2l11 protein. Here, we report that murine Morrbid lncRNA in hepatocytes participates in the regulation of proto-oncogene NRAS (neuroblastoma RAS viral oncogene homolog) splicing, including the formation of the isoform with PTC. We observed a significant increase of the NRAS isoform with PTC in hepatocytes with depleted Morrbid lncRNA. We demonstrated that the NRAS isoform with PTC is degraded via the NMD pathway. This transcript is presented almost only in the nucleus and has a half-life ~four times lower than other NRAS transcripts. Additionally, in UPF1 knockdown hepatocytes (the key NMD factor), we observed a significant increase of the NRAS isoform with PTC. By a modified capture hybridization (CHART) analysis of the protein targets, we uncovered interactions of Morrbid lncRNA with the SFPQ (splicing factor proline and glutamine rich)-NONO (non-POU domain-containing octamer-binding protein) splicing complex. Finally, we propose the regulation mechanism of NRAS splicing in murine hepatocytes by alternative splicing coupled with the NMD pathway with the input of Morrbid lncRNA.https://www.mdpi.com/1422-0067/21/16/5605alternative splicinglong noncoding RNAlivernonsense-mediated decay |
| spellingShingle | Anna Fefilova Pavel Melnikov Tatiana Prikazchikova Tatiana Abakumova Ilya Kurochkin Pavel V. Mazin Rustam Ziganshin Olga Sergeeva Timofei S. Zatsepin Murine Long Noncoding RNA Morrbid Contributes in the Regulation of NRAS Splicing in Hepatocytes In Vitro International Journal of Molecular Sciences alternative splicing long noncoding RNA liver nonsense-mediated decay |
| title | Murine Long Noncoding RNA Morrbid Contributes in the Regulation of NRAS Splicing in Hepatocytes In Vitro |
| title_full | Murine Long Noncoding RNA Morrbid Contributes in the Regulation of NRAS Splicing in Hepatocytes In Vitro |
| title_fullStr | Murine Long Noncoding RNA Morrbid Contributes in the Regulation of NRAS Splicing in Hepatocytes In Vitro |
| title_full_unstemmed | Murine Long Noncoding RNA Morrbid Contributes in the Regulation of NRAS Splicing in Hepatocytes In Vitro |
| title_short | Murine Long Noncoding RNA Morrbid Contributes in the Regulation of NRAS Splicing in Hepatocytes In Vitro |
| title_sort | murine long noncoding rna morrbid contributes in the regulation of nras splicing in hepatocytes in vitro |
| topic | alternative splicing long noncoding RNA liver nonsense-mediated decay |
| url | https://www.mdpi.com/1422-0067/21/16/5605 |
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