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Gene-specific transcript buffering revealed by perturbation of coactivator complexes
Open accessPublished version of a preprint
Abstract
Transcript buffering entails reciprocal modulation of mRNA synthesis and degradation to maintain stable RNA levels under varying cellular conditions. Current models depict a global connection between mRNA synthesis and degradation, but underlying mechanisms remain unclear. Here, we show that changes in RNA metabolism following depletion of TIP60/KAT5, the acetyltransferase subunit of the NuA4 transcriptional coactivator complex, reveal that transcript buffering occurs at a gene-specific level. By combining RNA sequencing of nuclear, cytoplasmic, and newly synthesized transcript fractions with biophysical modeling in mouse embryonic stem cells, we demonstrate that transcriptional changes caused by TIP60 depletion are offset by corresponding changes in RNA nuclear export and cytoplasmic stability, indicating gene-specific buffering. Disruption of the unrelated ATAC coactivator complex also causes gene-specific transcript buffering. We propose that cells dynamically adjust RNA splicing, export, and degradation in response to individual RNA synthesis alterations, thereby sustaining cellular homeostasis.
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Global quantification of mammalian gene expression control
Schwanhäusser, B., Busse, D., Li, N., Dittmar, G., Schuchhardt, J., Wolf, J., Chen, W., & Selbach, M. (2011) · Nature · doi:10.1038/nature10098 · Cited by 6,566 · cited 2×
“Furthermore, we assumed that the 24-hour auxin treatment was sufficiently long relative to the typical mRNA half-life, which is on the order of hours ( 28 , 29 ), allowing cells to attain a quasi-equilibrium state after perturbation.”
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“Furthermore, we assumed that the 24-hour auxin treatment was sufficiently long relative to the typical mRNA half-life, which is on the order of hours ( 28 , 29 ), allowing cells to attain a quasi-equilibrium state after perturbation.”
Gaidatzis, D., Burger, L., Florescu, M., & Stadler, M. B. (2015) · Nature Biotechnology · doi:10.1038/nbt.3269 · Cited by 313
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Metadata
- Authors
- Forouzanfar, F., Moreno, D. F., Plassard, D., Furst, A., Oliveira, K. A., Reina-San-Martin, B., Tora, L., Molina, N., & Mendoza, M.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.
- Corresponding author
- Molina, Nacho
- Mendoza, Manuel
- ORCID
- Venue
- Science Advances
- Published
- 2025-03-21
- Volume
- 11
- Issue
- 12
- Pages
- eadr1492-eadr1492
- ISSN
- 2375-2548 (ISSN-L)
- PMC
- PMC11922027
- OpenAlex
- W4408647752
- Cited by
- 3
- References
- 3
- Citations by year
- 2026: 1 · 2025: 2
- FWCI
- 0.90
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Science Advances (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- PubMed Central (submittedVersion)
- univOAK (4 institutions : Université de Strasbourg, Université de Haute Alsace, INSA Strasbourg, Bibliothèque Nationale et Universitaire de Strasbourg) (submittedVersion, cc-by)
- Funders
- Agence Nationale de la Recherche (ANR-22-CE11-0013, France2030, ANR-20-CE12-0014, ANR-10-IDEX-0002, ANR-10-INBS-0009, ANR-17-EURE-, ANR-22-CE12-0021, ANR-20-SFRI-0012, ANR‐10_INBS‐04, ANR-17-EURE-0023, ANR-10-IDEX, ANR-20-CE12, ANR-17, ANR-10, ANR-10-INBS-0004)
- Institut National de la Santé et de la Recherche Médicale (ANR 10 IDEX 0002, ANR-17-EURE-0023, ANR-20-SFRI-0012)
- Fondation pour la Recherche Médicale (ANR-10-INBS-04, EQU-2021-03012631)
- Université de Strasbourg (ANR-10-IDEX- 0002, ANR-17-EURE-0023, ITI 2021 2028, ANR-10-INBS-0009)
- Centre National de la Recherche Scientifique (ANR-10-IDEX-0002, 2021-2028)
- National Institutes of Health
- National Institute of General Medical Sciences (R35GM139564)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- mRNA synthesis, mRNA degradation, acetyltransferase, RNA nuclear export, RNA splicing, mouse embryonic stem cells, biophysical model
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