A ubiquitous GC content signature underlies multimodal mRNA regulation by DDX3X
Abstract The road from transcription to protein synthesis is paved with many obstacles, allowing for several modes of post-transcriptional regulation of gene expression. A fundamental player in mRNA biology is DDX3X, an RNA binding protein that canonically regulates mRNA translation. By monitoring d...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2024-01-01
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| Series: | Molecular Systems Biology |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/s44320-024-00013-0 |
| _version_ | 1797272258015657984 |
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| author | Ziad Jowhar Albert Xu Srivats Venkataramanan Francesco Dossena Mariah L Hoye Debra L Silver Stephen N Floor Lorenzo Calviello |
| author_facet | Ziad Jowhar Albert Xu Srivats Venkataramanan Francesco Dossena Mariah L Hoye Debra L Silver Stephen N Floor Lorenzo Calviello |
| author_sort | Ziad Jowhar |
| collection | DOAJ |
| description | Abstract The road from transcription to protein synthesis is paved with many obstacles, allowing for several modes of post-transcriptional regulation of gene expression. A fundamental player in mRNA biology is DDX3X, an RNA binding protein that canonically regulates mRNA translation. By monitoring dynamics of mRNA abundance and translation following DDX3X depletion, we observe stabilization of translationally suppressed mRNAs. We use interpretable statistical learning models to uncover GC content in the coding sequence as the major feature underlying RNA stabilization. This result corroborates GC content-related mRNA regulation detectable in other studies, including hundreds of ENCODE datasets and recent work focusing on mRNA dynamics in the cell cycle. We provide further evidence for mRNA stabilization by detailed analysis of RNA-seq profiles in hundreds of samples, including a Ddx3x conditional knockout mouse model exhibiting cell cycle and neurogenesis defects. Our study identifies a ubiquitous feature underlying mRNA regulation and highlights the importance of quantifying multiple steps of the gene expression cascade, where RNA abundance and protein production are often uncoupled. |
| first_indexed | 2024-03-07T14:24:50Z |
| format | Article |
| id | doaj.art-06f4cd09b9774f419e1aed0fab3425ff |
| institution | Directory Open Access Journal |
| issn | 1744-4292 |
| language | English |
| last_indexed | 2024-03-07T14:24:50Z |
| publishDate | 2024-01-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | Molecular Systems Biology |
| spelling | doaj.art-06f4cd09b9774f419e1aed0fab3425ff2024-03-06T08:06:06ZengSpringer NatureMolecular Systems Biology1744-42922024-01-0120327629010.1038/s44320-024-00013-0A ubiquitous GC content signature underlies multimodal mRNA regulation by DDX3XZiad Jowhar0Albert Xu1Srivats Venkataramanan2Francesco Dossena3Mariah L Hoye4Debra L Silver5Stephen N Floor6Lorenzo Calviello7Department of Cell and Tissue Biology, UCSFDepartment of Cell and Tissue Biology, UCSFDepartment of Cell and Tissue Biology, UCSFHuman TechnopoleDepartment of Molecular Genetics and Microbiology, Duke University Medical CenterDepartment of Molecular Genetics and Microbiology, Duke University Medical CenterDepartment of Cell and Tissue Biology, UCSFHuman TechnopoleAbstract The road from transcription to protein synthesis is paved with many obstacles, allowing for several modes of post-transcriptional regulation of gene expression. A fundamental player in mRNA biology is DDX3X, an RNA binding protein that canonically regulates mRNA translation. By monitoring dynamics of mRNA abundance and translation following DDX3X depletion, we observe stabilization of translationally suppressed mRNAs. We use interpretable statistical learning models to uncover GC content in the coding sequence as the major feature underlying RNA stabilization. This result corroborates GC content-related mRNA regulation detectable in other studies, including hundreds of ENCODE datasets and recent work focusing on mRNA dynamics in the cell cycle. We provide further evidence for mRNA stabilization by detailed analysis of RNA-seq profiles in hundreds of samples, including a Ddx3x conditional knockout mouse model exhibiting cell cycle and neurogenesis defects. Our study identifies a ubiquitous feature underlying mRNA regulation and highlights the importance of quantifying multiple steps of the gene expression cascade, where RNA abundance and protein production are often uncoupled.https://doi.org/10.1038/s44320-024-00013-0TranscriptomicsDDX3XmRNA BiologyTranslationComputational Biology |
| spellingShingle | Ziad Jowhar Albert Xu Srivats Venkataramanan Francesco Dossena Mariah L Hoye Debra L Silver Stephen N Floor Lorenzo Calviello A ubiquitous GC content signature underlies multimodal mRNA regulation by DDX3X Molecular Systems Biology Transcriptomics DDX3X mRNA Biology Translation Computational Biology |
| title | A ubiquitous GC content signature underlies multimodal mRNA regulation by DDX3X |
| title_full | A ubiquitous GC content signature underlies multimodal mRNA regulation by DDX3X |
| title_fullStr | A ubiquitous GC content signature underlies multimodal mRNA regulation by DDX3X |
| title_full_unstemmed | A ubiquitous GC content signature underlies multimodal mRNA regulation by DDX3X |
| title_short | A ubiquitous GC content signature underlies multimodal mRNA regulation by DDX3X |
| title_sort | ubiquitous gc content signature underlies multimodal mrna regulation by ddx3x |
| topic | Transcriptomics DDX3X mRNA Biology Translation Computational Biology |
| url | https://doi.org/10.1038/s44320-024-00013-0 |
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