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Cited by 14Pluripotent Stem Cells ResearchEpigenetics and DNA MethylationDevelopmental Biology and Gene Regulation

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The cytoplasmic fraction of the histone lysine methyltransferase Setdb1 is essential for embryonic stem cells

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Rapone, Roberta, Del Maestro, Laurence, Bouyioukos, Costas, Albini, Sonia, Cruz-Tapias, Paola, Joliot, Véronique, Cosson, Bertrand, Ait-Si-Ali, Slimane·2023·iScience
DOI 10.1016/j.isci.2023.107386PMC PMC10407132

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Abstract

Abstract Embryonic stem cells (ESCs) fate is regulated both at transcriptional and post-transcriptional levels. Indeed, several studies showed that, in addition to gene transcription, mRNA stability and protein synthesis are finely tuned and strongly control the ESCs pluripotency and fate changes. An increasing number of RNA-binding proteins (RBPs) involved in post-transcriptional and translational regulation of gene expression has been identified as regulators of ESC identity. The major lysine methyltransferase Setdb1 is essential for the self-renewal and viability of ESCs. Setdb1 was primarily known to methylate the lysine 9 of histone 3 (H3K9) in the nucleus, where it regulates chromatin functions. However, Setdb1 is also massively localized in the cytoplasm, including in mouse ESCs, where its role remains unknown. Here we show that the cytoplasmic Setdb1 (cSetdb1) is essential for the survival of mESCs. Functional assays further demonstrate that cSetdb1 regulates gene expression post-transcriptionally, affecting the abundance of mRNAs and the rate of newly synthetized proteins. A yeast-two-hybrid assay shows that cSetdb1 interacts with several regulators of mRNA stability and protein translation machinery, such as the ESCs-specific E3 ubiquitin ligase and mRNA silencer Trim71/Lin41. Finally, proteomic analyses reveal that cSetdb1 is required for the integrity of Trim71 complexes involved in mRNA metabolism and translation. Altogether, our data uncover the essential cytoplasmic function of a firstly supposed nuclear “histone” lysine methyltransferase, Setdb1, and provide new insights into the cytoplasmic/post-transcriptional regulation of gene expression mediated by a key epigenetic regulator.

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Metadata

Authors
Rapone, R., Del Maestro, L., Bouyioukos, C., Albini, S., Cruz-Tapias, P., Joliot, V., Cosson, B., & Ait-Si-Ali, S.
Affiliations
Centre National de la Recherche Scientifique (FR)
Corresponding author
Cosson, Bertrand
ORCID
Venue
iScience
Publisher
Elsevier BV
Published
2023-08
Volume
26
Issue
8
Pages
107386
ISSN
2589-0042 (ISSN-L)
DOI
10.1016/j.isci.2023.107386
PMC
PMC10407132
OpenAlex
W4384157160
Cited by
14
References
3
Citations by year
2026: 6 · 2025: 6 · 2024: 2
FWCI
1.25
Type
journal article
Language
en
Open access
Licence
Locations
  • iScience (publishedVersion, cc-by-nc-nd)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
  • HAL (submittedVersion, other-oa)
  • HAL (submittedVersion, cc-by-nc)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Association française contre les myopathies
  • Fondation pour la Recherche Médicale (DEQ20160334922)
  • Agence Nationale de la Recherche (ANR-17-CE12-0010-01)
  • Université Paris Diderot (ANR-11-LABX-0071)
  • Universidad del Rosario
  • Fondation ARC pour la Recherche sur le Cancer
  • Departamento Administrativo de Ciencia, Tecnología e Innovación
  • Labex
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords
SETDB1, embryonic stem cells, lysine methyltransferase, H3K9 methylation, mRNA stability, post-transcriptional regulation, E3 ubiquitin ligase, mRNA translation, self-renewal, epigenetic regulation, mRNA metabolism

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