Estrogen receptor alpha controls gene expression via translational offsetting
Open accessPreprint — published as 10.15252/embj.2018101323 · Paper page
Abstract
Estrogen receptor alpha (ERα) activity is associated with increased cancer cell proliferation. Studies aiming to understand the impact of ERα on cancer-associated phenotypes have largely been limited to its transcriptional activity. Herein, we demonstrate that ERα coordinates its transcriptional output with selective modulation of mRNA translation. Importantly, translational perturbations caused by depletion of ERα largely manifest as “translational offsetting” of the transcriptome, whereby amounts of translated mRNA and protein levels are maintained constant despite changes in mRNA abundance. Transcripts whose levels, but not polysome-association, are reduced following ERα depletion lack features which limit translational efficiency including structured 5’UTRs and miRNA target sites. In contrast, mRNAs induced upon ERα depletion whose polysome-association remains unaltered are enriched in codons requiring U34-modified tRNAs for efficient decoding. Consistently, ERα regulates levels of U34-modification enzymes, whereas altered expression of U34-modification enzymes disrupts ERα dependent translational offsetting. Altogether, we unravel a hitherto unprecedented mechanism of ERα-dependent orchestration of transcriptional and translational programs, and highlight that translational offsetting may be a pervasive mechanism of proteome maintenance in hormone-dependent cancers.
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Helzer, K. T., Ozers, M. S., Meyer, M. B., Benkusky, N. A., Solodin, N. M., Reese, R., Warren, C. L., Pike, J. W., & Alarid, E. T. (2018) · Molecular and Cellular Biology · doi:10.1128/mcb.00417-18 · Cited by 34 · see citing works
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Translational compensation of gene copy number alterations by aneuploidy in Drosophila melanogaster
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Megas, G., Chrisofos, M., Anastasiou, I. P., Tsitlidou, A., Choreftaki, T., & Deliveliotis, C. N. (2014) · Asian Journal of Andrology · doi:10.4103/1008-682x.136445 · Cited by 15 · see citing works
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Ribosome Profiling: Global Views of TranslationPreprint
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Selective inhibitors of mTORC1 activate 4EBP1 and suppress tumor growth
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Self-citationTranslational offsetting as a mode of estrogen receptor α‐dependent regulation of gene expression
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Chaparro, V., Leroux, L., Masvidal, L., Lorent, J., Graber, T. E., Zimmermann, A., Duque, G. A., Descoteaux, A., Alain, T., Larsson, O. S., et al. (2020) · PLoS Pathogens · doi:10.1371/journal.ppat.1008291 · Cited by 40 · see citing works
Self-citationMNK2 governs the macrophage antiinflammatory phenotype
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7SK methylation by METTL3 promotes transcriptional activity
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Regulation of mRNA Translation by Hormone Receptors in Breast and Prostate Cancer
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Disease-associated inosine misincorporation into RNA hinders translation
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A ubiquitous GC content signature underlies multimodal mRNA regulation by DDX3X
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Exploring edible bird nest's potential in mitigating Wi‐Fi's impact on male reproductive health
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Characterization of m6A Modifiers and RNA Modifications in Uterine Fibroids
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Posttranscriptional reprogramming controls MASLD progression through chronic ER stress adaptation
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More or less – the same? mRNA fluctuations are balanced during translation
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Epigenetic coordination of transcriptional and translational programs in hypoxiaPreprint
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Self-citationCXXC5 is a ubiquitinated protein and is degraded by the ubiquitination-proteasome pathwayPreprint
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Regulation of mRNA translation during the inflammatory response in murine macrophages
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Both, D., Derks, I., Vanleyssem, R., Leclercq, M., Hachem, N. E., Close, P., Eldering, E., & Haselager, M. (2026) · Molecular Oncology · doi:10.1002/1878-0261.70328
- Authors
- Lorent, J., Rebello, R. J., Hoef, V. V., Lawrence, M. G., Szkop, K. J., Kusnadi, E., Samreen, B., Balanathan, P., Scharmann, K., Takizawa, I., Leidel, S. A., Risbridger, G. P., Topisirovic, I., Larsson, O., & Furic, L.
- Affiliations
- Science for Life Laboratory (SE)
- Peter MacCallum Cancer Centre (AU)
- The University of Melbourne (AU)
- Monash University (AU)
- University of Münster (DE)
- University of Bern (CH)
- Corresponding author
- Larsson, Ola
- Furic, Luc
- ORCID
- Venue
- The EMBO Journal
- Publisher
- openRxiv
- Published
- 2018-12-28
- Volume
- 38
- Issue
- 23
- Pages
- e101323-e101323
- ISSN
- 0261-4189 (ISSN-L)
- PMC
- PMC6885737
- OpenAlex
- W2975051965
- Cited by
- 46
- References
- 97
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 6 · 2023: 9 · 2022: 5 · 2021: 8 · 2020: 6 · 2019: 2 · 2018: 1
- FWCI
- 3.16
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The EMBO Journal (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Bern Open Repository and Information System (University of Bern) (submittedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- Minerva Access (University of Melbourne) (submittedVersion)
- ORBi (University of Liège) (submittedVersion)
- Funders
- U.S. Department of Health and Human Services
- Victorian Cancer Agency (MCRF16007)
- Marshfield Clinic Research Foundation
- Department of Health and Human Services, State Government of Victoria (MCRF16007, MCRF18017)
- Government of Canada (MOP-363027)
- Deutsche Forschungsgemeinschaft (LE 3260/3-1)
- Swedish Foundation for International Cooperation in Research and Higher Education (IG2012-2073)
- Cancerfonden (2016/526)
- Karolinska Institutet
- Knut och Alice Wallenbergs Stiftelse (2013.0181)
- Vetenskapsrådet (2016-02891)
- Cancerföreningen i Stockholm (151153)
- Science for Life Laboratory
- Walloon excellence in life sciences and biotechnology
- National Institutes of Health
- Canadian Institutes of Health Research (MOP-363027)
- Fonds de Recherche du Québec - Santé (34872)
- National Health and Medical Research Council (1145777, 1102752, 1141339)
- National Cancer Institute (R01CA202021)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Keywords
- estrogen receptor alpha, mRNA translation, transcriptional regulation, tRNA modification enzymes, microRNA binding sites, polysome association, hormone-dependent tumors, tumor cell proliferation
- MeSH terms
- Breast Neoplasms, Female, Humans, Polyribosomes, RNA, Messenger, Protein Biosynthesis, Signal Transduction, Transcriptional Activation, Gene Expression Regulation, Neoplastic, Estrogen Receptor alpha, Cell Proliferation, MCF-7 Cells
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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