Passive shaping of intra- and intercellular m6A dynamics via mRNA metabolism
m6A is the most widespread mRNA modification and is primarily implicated in controlling mRNA stability. Fundamental questions pertaining to m6A are the extent to which it is dynamically modulated within cells and across stimuli, and the forces underlying such modulation. Prior work has focused on in...
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| Format: | Article |
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eLife Sciences Publications Ltd
2025-06-01
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| Online Access: | https://elifesciences.org/articles/100448 |
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| author | David Dierks Ran Shachar Ronit Nir Miguel Angel Garcia-Campos Anna Uzonyi David Wiener Ursula Toth Walter Rossmanith Lior Lasman Boris Slobodin Jacob H Hanna Yaron Antebi Ruth Scherz-Shouval Schraga Schwartz |
| author_facet | David Dierks Ran Shachar Ronit Nir Miguel Angel Garcia-Campos Anna Uzonyi David Wiener Ursula Toth Walter Rossmanith Lior Lasman Boris Slobodin Jacob H Hanna Yaron Antebi Ruth Scherz-Shouval Schraga Schwartz |
| author_sort | David Dierks |
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| description | m6A is the most widespread mRNA modification and is primarily implicated in controlling mRNA stability. Fundamental questions pertaining to m6A are the extent to which it is dynamically modulated within cells and across stimuli, and the forces underlying such modulation. Prior work has focused on investigating active mechanisms governing m6A levels, such as recruitment of m6A writers or erasers leading to either ‘global’ or ‘site-specific’ modulation. Here, we propose that changes in m6A levels across subcellular compartments and biological trajectories may result from passive changes in gene-level mRNA metabolism. To predict the intricate interdependencies between m6A levels, mRNA localization, and mRNA decay, we establish a differential model ‘m6ADyn’ encompassing mRNA transcription, methylation, export, and m6A-dependent and -independent degradation. We validate the predictions of m6ADyn in the context of intracellular m6A dynamics, where m6ADyn predicts associations between relative mRNA localization and m6A levels, which we experimentally confirm. We further explore m6ADyn predictions pertaining to changes in m6A levels upon controlled perturbations of mRNA metabolism, which we also experimentally confirm. Finally, we demonstrate the relevance of m6ADyn in the context of cellular heat stress response, where genes subjected to altered mRNA product and export also display predictable changes in m6A levels, consistent with m6ADyn predictions. Our findings establish a framework for dissecting m6A dynamics and suggest the role of passive dynamics in shaping m6A levels in mammalian systems. |
| format | Article |
| id | doaj-art-348a01fcb50e4c15a40cc59e493bb8d0 |
| institution | Kabale University |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-06-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj-art-348a01fcb50e4c15a40cc59e493bb8d02025-08-20T03:29:18ZengeLife Sciences Publications LtdeLife2050-084X2025-06-011310.7554/eLife.100448Passive shaping of intra- and intercellular m6A dynamics via mRNA metabolismDavid Dierks0https://orcid.org/0000-0003-1515-7222Ran Shachar1Ronit Nir2Miguel Angel Garcia-Campos3Anna Uzonyi4David Wiener5https://orcid.org/0000-0002-7435-4253Ursula Toth6Walter Rossmanith7Lior Lasman8Boris Slobodin9Jacob H Hanna10Yaron Antebi11https://orcid.org/0000-0002-5771-6814Ruth Scherz-Shouval12https://orcid.org/0000-0002-4570-121XSchraga Schwartz13https://orcid.org/0000-0002-3671-9709Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, IsraelDepartment of Molecular Genetics, Weizmann Institute of Science, Rehovot, IsraelDepartment of Molecular Genetics, Weizmann Institute of Science, Rehovot, IsraelDepartment of Molecular Genetics, Weizmann Institute of Science, Rehovot, IsraelDepartment of Molecular Genetics, Weizmann Institute of Science, Rehovot, IsraelDepartment of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel; Center for Environmental Genomics, University of Washington, Seattle, United StatesCenter for Anatomy & Cell Biology, Medical University of Vienna, Vienna, AustriaCenter for Anatomy & Cell Biology, Medical University of Vienna, Vienna, AustriaDepartment of Molecular Genetics, Weizmann Institute of Science, Rehovot, IsraelDepartment of Biochemistry, Rappaport Faculty of Medicine, Technion, Haifa, IsraelDepartment of Molecular Genetics, Weizmann Institute of Science, Rehovot, IsraelDepartment of Molecular Genetics, Weizmann Institute of Science, Rehovot, IsraelDepartment of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, IsraelDepartment of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israelm6A is the most widespread mRNA modification and is primarily implicated in controlling mRNA stability. Fundamental questions pertaining to m6A are the extent to which it is dynamically modulated within cells and across stimuli, and the forces underlying such modulation. Prior work has focused on investigating active mechanisms governing m6A levels, such as recruitment of m6A writers or erasers leading to either ‘global’ or ‘site-specific’ modulation. Here, we propose that changes in m6A levels across subcellular compartments and biological trajectories may result from passive changes in gene-level mRNA metabolism. To predict the intricate interdependencies between m6A levels, mRNA localization, and mRNA decay, we establish a differential model ‘m6ADyn’ encompassing mRNA transcription, methylation, export, and m6A-dependent and -independent degradation. We validate the predictions of m6ADyn in the context of intracellular m6A dynamics, where m6ADyn predicts associations between relative mRNA localization and m6A levels, which we experimentally confirm. We further explore m6ADyn predictions pertaining to changes in m6A levels upon controlled perturbations of mRNA metabolism, which we also experimentally confirm. Finally, we demonstrate the relevance of m6ADyn in the context of cellular heat stress response, where genes subjected to altered mRNA product and export also display predictable changes in m6A levels, consistent with m6ADyn predictions. Our findings establish a framework for dissecting m6A dynamics and suggest the role of passive dynamics in shaping m6A levels in mammalian systems.https://elifesciences.org/articles/100448m6AepitranscriptomedynamicsmodelRNA-seq |
| spellingShingle | David Dierks Ran Shachar Ronit Nir Miguel Angel Garcia-Campos Anna Uzonyi David Wiener Ursula Toth Walter Rossmanith Lior Lasman Boris Slobodin Jacob H Hanna Yaron Antebi Ruth Scherz-Shouval Schraga Schwartz Passive shaping of intra- and intercellular m6A dynamics via mRNA metabolism eLife m6A epitranscriptome dynamics model RNA-seq |
| title | Passive shaping of intra- and intercellular m6A dynamics via mRNA metabolism |
| title_full | Passive shaping of intra- and intercellular m6A dynamics via mRNA metabolism |
| title_fullStr | Passive shaping of intra- and intercellular m6A dynamics via mRNA metabolism |
| title_full_unstemmed | Passive shaping of intra- and intercellular m6A dynamics via mRNA metabolism |
| title_short | Passive shaping of intra- and intercellular m6A dynamics via mRNA metabolism |
| title_sort | passive shaping of intra and intercellular m6a dynamics via mrna metabolism |
| topic | m6A epitranscriptome dynamics model RNA-seq |
| url | https://elifesciences.org/articles/100448 |
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