The transcription factor DUX4 orchestrates translational reprogramming by broadly suppressing translation efficiency and promoting expression of DUX4-induced mRNAs.
Translational control is critical for cell fate transitions during development, lineage specification, and tumorigenesis. Here, we show that the transcription factor double homeobox protein 4 (DUX4), and its previously characterized transcriptional program, broadly regulates translation to change th...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2023-09-01
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| Series: | PLoS Biology |
| Online Access: | https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.3002317&type=printable |
| _version_ | 1827352792490049536 |
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| author | Danielle C Hamm Ellen M Paatela Sean R Bennett Chao-Jen Wong Amy E Campbell Cynthia L Wladyka Andrew A Smith Sujatha Jagannathan Andrew C Hsieh Stephen J Tapscott |
| author_facet | Danielle C Hamm Ellen M Paatela Sean R Bennett Chao-Jen Wong Amy E Campbell Cynthia L Wladyka Andrew A Smith Sujatha Jagannathan Andrew C Hsieh Stephen J Tapscott |
| author_sort | Danielle C Hamm |
| collection | DOAJ |
| description | Translational control is critical for cell fate transitions during development, lineage specification, and tumorigenesis. Here, we show that the transcription factor double homeobox protein 4 (DUX4), and its previously characterized transcriptional program, broadly regulates translation to change the cellular proteome. DUX4 is a key regulator of zygotic genome activation in human embryos, whereas misexpression of DUX4 causes facioscapulohumeral muscular dystrophy (FSHD) and is associated with MHC-I suppression and immune evasion in cancer. We report that translation initiation and elongation factors are disrupted downstream of DUX4 expression in human myoblasts. Genome-wide translation profiling identified mRNAs susceptible to DUX4-induced translation inhibition, including those encoding antigen presentation factors and muscle lineage proteins, while DUX4-induced mRNAs were robustly translated. Endogenous expression of DUX4 in human FSHD myotubes and cancer cell lines also correlated with reduced protein synthesis and MHC-I presentation. Our findings reveal that DUX4 orchestrates cell state conversion by suppressing the cellular proteome while maintaining translation of DUX4-induced mRNAs to promote an early developmental program. |
| first_indexed | 2024-03-08T03:11:12Z |
| format | Article |
| id | doaj.art-d4c23a7364914eb7b4d54ecba0e43e3c |
| institution | Directory Open Access Journal |
| issn | 1544-9173 1545-7885 |
| language | English |
| last_indexed | 2024-03-08T03:11:12Z |
| publishDate | 2023-09-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj.art-d4c23a7364914eb7b4d54ecba0e43e3c2024-02-13T05:30:53ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852023-09-01219e300231710.1371/journal.pbio.3002317The transcription factor DUX4 orchestrates translational reprogramming by broadly suppressing translation efficiency and promoting expression of DUX4-induced mRNAs.Danielle C HammEllen M PaatelaSean R BennettChao-Jen WongAmy E CampbellCynthia L WladykaAndrew A SmithSujatha JagannathanAndrew C HsiehStephen J TapscottTranslational control is critical for cell fate transitions during development, lineage specification, and tumorigenesis. Here, we show that the transcription factor double homeobox protein 4 (DUX4), and its previously characterized transcriptional program, broadly regulates translation to change the cellular proteome. DUX4 is a key regulator of zygotic genome activation in human embryos, whereas misexpression of DUX4 causes facioscapulohumeral muscular dystrophy (FSHD) and is associated with MHC-I suppression and immune evasion in cancer. We report that translation initiation and elongation factors are disrupted downstream of DUX4 expression in human myoblasts. Genome-wide translation profiling identified mRNAs susceptible to DUX4-induced translation inhibition, including those encoding antigen presentation factors and muscle lineage proteins, while DUX4-induced mRNAs were robustly translated. Endogenous expression of DUX4 in human FSHD myotubes and cancer cell lines also correlated with reduced protein synthesis and MHC-I presentation. Our findings reveal that DUX4 orchestrates cell state conversion by suppressing the cellular proteome while maintaining translation of DUX4-induced mRNAs to promote an early developmental program.https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.3002317&type=printable |
| spellingShingle | Danielle C Hamm Ellen M Paatela Sean R Bennett Chao-Jen Wong Amy E Campbell Cynthia L Wladyka Andrew A Smith Sujatha Jagannathan Andrew C Hsieh Stephen J Tapscott The transcription factor DUX4 orchestrates translational reprogramming by broadly suppressing translation efficiency and promoting expression of DUX4-induced mRNAs. PLoS Biology |
| title | The transcription factor DUX4 orchestrates translational reprogramming by broadly suppressing translation efficiency and promoting expression of DUX4-induced mRNAs. |
| title_full | The transcription factor DUX4 orchestrates translational reprogramming by broadly suppressing translation efficiency and promoting expression of DUX4-induced mRNAs. |
| title_fullStr | The transcription factor DUX4 orchestrates translational reprogramming by broadly suppressing translation efficiency and promoting expression of DUX4-induced mRNAs. |
| title_full_unstemmed | The transcription factor DUX4 orchestrates translational reprogramming by broadly suppressing translation efficiency and promoting expression of DUX4-induced mRNAs. |
| title_short | The transcription factor DUX4 orchestrates translational reprogramming by broadly suppressing translation efficiency and promoting expression of DUX4-induced mRNAs. |
| title_sort | transcription factor dux4 orchestrates translational reprogramming by broadly suppressing translation efficiency and promoting expression of dux4 induced mrnas |
| url | https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.3002317&type=printable |
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