In Vivo RNAi-Mediated eIF3m Knockdown Affects Ribosome Biogenesis and Transcription but Has Limited Impact on mRNA-Specific Translation
© 2019 Translation is an essential biological process, and dysregulation is associated with a range of diseases including ribosomopathies, diabetes, and cancer. Here, we examine translation dysregulation in vivo using RNAi to knock down the m-subunit of the translation initiation factor eIF3 in the...
| Main Authors: | , , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | English |
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Elsevier BV
2021
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| Online Access: | https://hdl.handle.net/1721.1/136581 |
| _version_ | 1811077304000970752 |
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| author | Smekalova, Elena M Gerashchenko, Maxim V O’Connor, Patrick BF Whittaker, Charles A Kauffman, Kevin J Fefilova, Anna S Zatsepin, Timofei S Bogorad, Roman L Baranov, Pavel V Langer, Robert Gladyshev, Vadim N Anderson, Daniel G Koteliansky, Victor |
| author2 | Koch Institute for Integrative Cancer Research at MIT |
| author_facet | Koch Institute for Integrative Cancer Research at MIT Smekalova, Elena M Gerashchenko, Maxim V O’Connor, Patrick BF Whittaker, Charles A Kauffman, Kevin J Fefilova, Anna S Zatsepin, Timofei S Bogorad, Roman L Baranov, Pavel V Langer, Robert Gladyshev, Vadim N Anderson, Daniel G Koteliansky, Victor |
| author_sort | Smekalova, Elena M |
| collection | MIT |
| description | © 2019 Translation is an essential biological process, and dysregulation is associated with a range of diseases including ribosomopathies, diabetes, and cancer. Here, we examine translation dysregulation in vivo using RNAi to knock down the m-subunit of the translation initiation factor eIF3 in the mouse liver. Transcriptome sequencing, ribosome profiling, whole proteome, and phosphoproteome analyses show that eIF3m deficiency leads to the transcriptional response and changes in cellular translation that yield few detectable differences in the translation of particular mRNAs. The transcriptional response fell into two main categories: ribosome biogenesis (increased transcription of ribosomal proteins) and cell metabolism (alterations in lipid, amino acid, nucleic acid, and drug metabolism). Analysis of ribosome biogenesis reveals inhibition of rRNA processing, highlighting decoupling of rRNA synthesis and ribosomal protein gene transcription in response to eIF3m knockdown. Interestingly, a similar reduction in eIF3m protein levels is associated with induction of the mTOR pathway in vitro but not in vivo. Overall, this work highlights the utility of a RNAi-based in vivo approach for studying the regulation of mammalian translation in vivo. |
| first_indexed | 2024-09-23T10:40:50Z |
| format | Article |
| id | mit-1721.1/136581 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T10:40:50Z |
| publishDate | 2021 |
| publisher | Elsevier BV |
| record_format | dspace |
| spelling | mit-1721.1/1365812024-03-20T18:59:54Z In Vivo RNAi-Mediated eIF3m Knockdown Affects Ribosome Biogenesis and Transcription but Has Limited Impact on mRNA-Specific Translation Smekalova, Elena M Gerashchenko, Maxim V O’Connor, Patrick BF Whittaker, Charles A Kauffman, Kevin J Fefilova, Anna S Zatsepin, Timofei S Bogorad, Roman L Baranov, Pavel V Langer, Robert Gladyshev, Vadim N Anderson, Daniel G Koteliansky, Victor Koch Institute for Integrative Cancer Research at MIT Massachusetts Institute of Technology. Department of Chemical Engineering Harvard University--MIT Division of Health Sciences and Technology Massachusetts Institute of Technology. Institute for Medical Engineering & Science © 2019 Translation is an essential biological process, and dysregulation is associated with a range of diseases including ribosomopathies, diabetes, and cancer. Here, we examine translation dysregulation in vivo using RNAi to knock down the m-subunit of the translation initiation factor eIF3 in the mouse liver. Transcriptome sequencing, ribosome profiling, whole proteome, and phosphoproteome analyses show that eIF3m deficiency leads to the transcriptional response and changes in cellular translation that yield few detectable differences in the translation of particular mRNAs. The transcriptional response fell into two main categories: ribosome biogenesis (increased transcription of ribosomal proteins) and cell metabolism (alterations in lipid, amino acid, nucleic acid, and drug metabolism). Analysis of ribosome biogenesis reveals inhibition of rRNA processing, highlighting decoupling of rRNA synthesis and ribosomal protein gene transcription in response to eIF3m knockdown. Interestingly, a similar reduction in eIF3m protein levels is associated with induction of the mTOR pathway in vitro but not in vivo. Overall, this work highlights the utility of a RNAi-based in vivo approach for studying the regulation of mammalian translation in vivo. 2021-10-27T20:36:05Z 2021-10-27T20:36:05Z 2020 2021-06-03T17:38:53Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/136581 en 10.1016/J.OMTN.2019.11.009 Molecular Therapy – Nucleic Acids Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier BV Elsevier |
| spellingShingle | Smekalova, Elena M Gerashchenko, Maxim V O’Connor, Patrick BF Whittaker, Charles A Kauffman, Kevin J Fefilova, Anna S Zatsepin, Timofei S Bogorad, Roman L Baranov, Pavel V Langer, Robert Gladyshev, Vadim N Anderson, Daniel G Koteliansky, Victor In Vivo RNAi-Mediated eIF3m Knockdown Affects Ribosome Biogenesis and Transcription but Has Limited Impact on mRNA-Specific Translation |
| title | In Vivo RNAi-Mediated eIF3m Knockdown Affects Ribosome Biogenesis and Transcription but Has Limited Impact on mRNA-Specific Translation |
| title_full | In Vivo RNAi-Mediated eIF3m Knockdown Affects Ribosome Biogenesis and Transcription but Has Limited Impact on mRNA-Specific Translation |
| title_fullStr | In Vivo RNAi-Mediated eIF3m Knockdown Affects Ribosome Biogenesis and Transcription but Has Limited Impact on mRNA-Specific Translation |
| title_full_unstemmed | In Vivo RNAi-Mediated eIF3m Knockdown Affects Ribosome Biogenesis and Transcription but Has Limited Impact on mRNA-Specific Translation |
| title_short | In Vivo RNAi-Mediated eIF3m Knockdown Affects Ribosome Biogenesis and Transcription but Has Limited Impact on mRNA-Specific Translation |
| title_sort | in vivo rnai mediated eif3m knockdown affects ribosome biogenesis and transcription but has limited impact on mrna specific translation |
| url | https://hdl.handle.net/1721.1/136581 |
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