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

Roberta Rapone; Laurence Del Maestro; Costas Bouyioukos; Sonia Albini; Paola Cruz-Tapias; Véronique Joliot; Bertrand Cosson; Slimane Ait-Si-Ali

doi:10.1016/j.isci.2023.107386

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

iScience. 2023 Jul 14;26(8):107386. doi: 10.1016/j.isci.2023.107386. eCollection 2023 Aug 18.

Authors

Roberta Rapone¹, Laurence Del Maestro¹, Costas Bouyioukos¹, Sonia Albini¹, Paola Cruz-Tapias¹, Véronique Joliot¹, Bertrand Cosson¹, Slimane Ait-Si-Ali¹

Affiliation

¹ Université Paris Cité, CNRS, Epigenetics and Cell Fate, UMR7216, 75013 Paris, France.

Abstract

The major lysine methyltransferase (KMT) Setdb1 is essential for self-renewal and viability of mouse embryonic stem cells (mESCs). 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 mESCs, where its role remains elusive. Here, we show that the cytoplasmic Setdb1 (cSetdb1) is essential for the survival of mESCs. Yeast two-hybrid analysis revealed 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. We found that cSetdb1 is required for the integrity of Trim71 complex(es) involved in mRNA metabolism and translation. cSetdb1 modulates the abundance of mRNAs and the rate of newly synthesized proteins. Altogether, our data uncovered the cytoplasmic post-transcriptional regulation of gene expression mediated by a key epigenetic regulator.

Keywords: Biological sciences; Cell biology; Epigenetics; Molecular biology; Molecular mechanism of gene regulation; Natural sciences; Stem cells research.