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RSL24D1 sustains steady-state ribosome biogenesis and pluripotency translational programs in embryonic stem cells.

ABSTRACT: Embryonic stem cell (ESC) fate decisions are regulated by a complex circuitry that coordinates gene expression at multiple levels from chromatin to mRNA processing. Recently, ribosome biogenesis and translation have emerged as key pathways that efficiently control stem cell homeostasis, yet the underlying molecular mechanisms remain largely unknown. Here, we identified RSL24D1 as highly expressed in both mouse and human pluripotent stem cells. RSL24D1 is associated with nuclear pre-ribosomes and is required for the biogenesis of 60S subunits in mouse ESCs. Interestingly, RSL24D1 depletion significantly impairs global translation, particularly of key pluripotency factors and of components from the Polycomb Repressive Complex 2 (PRC2). While having a moderate impact on differentiation, RSL24D1 depletion significantly alters ESC self-renewal and lineage commitment choices. Altogether, these results demonstrate that RSL24D1-dependant ribosome biogenesis is both required to sustain the expression of pluripotent transcriptional programs and to silence PRC2-regulated developmental programs, which concertedly dictate ESC homeostasis.

SUBMITTER: Durand S

PROVIDER: S-EPMC9870888 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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RSL24D1 sustains steady-state ribosome biogenesis and pluripotency translational programs in embryonic stem cells.

Durand Sébastien S Bruelle Marion M Bourdelais Fleur F Bennychen Bigitha B Blin-Gonthier Juliana J Isaac Caroline C Huyghe Aurélia A Martel Sylvie S Seyve Antoine A Vanbelle Christophe C Adrait Annie A Couté Yohann Y Meyronet David D Catez Frédéric F Diaz Jean-Jacques JJ Lavial Fabrice F Ricci Emiliano P EP Ducray François F Gabut Mathieu M

Nature communications 20230123 1

Embryonic stem cell (ESC) fate decisions are regulated by a complex circuitry that coordinates gene expression at multiple levels from chromatin to mRNA processing. Recently, ribosome biogenesis and translation have emerged as key pathways that efficiently control stem cell homeostasis, yet the underlying molecular mechanisms remain largely unknown. Here, we identified RSL24D1 as highly expressed in both mouse and human pluripotent stem cells. RSL24D1 is associated with nuclear pre-ribosomes and ...[more]

PMID: 36690642

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Project description:Transcription factor EB (TFEB), a well-known master regulator of autophagy and lysosomal biogenesis, is a member of the microphthalmia family of transcription factors (MiT family). Over the years, TFEB has been shown to have diverse roles in various physiological processes such as clearance for intracellular pathogenic factors and having developmental functions such as dendritic maturation, as well as osteoclast, and endoderm differentiation. However, in the present study, we propose a novel mechanism for TFEB governing pluripotency of mouse ESCs (mESCs) by regulating the pluripotency transcriptional network (PTN) in these cells. We observed high levels of TFEB mRNA and protein levels in undifferentiated mESCs. Interestingly, we found a reduction of Nanog and Sox2 levels in TFEB knockout (KO) mESCs while pluripotency was maintained as there was an upregulation of TFE3, a potent stem cell maintenance factor. In consistent, double knockout of TFEB/TFE3 (TFEB/3 DKO) reduced mESC pluripotency, as indicated by the loss of ESC morphology, reduction of ESC markers, and the emergence of differentiation markers. We further discovered that Nanog was a TFEB target gene in undifferentiated mESCs. TFEB also promoted sex-determining region Y-box2 (Sox2) transcription by forming a heterodimer with Sox2 in mESCs. Notably, Sox2, Oct4, and Nanog were also binding to the TFEB promoter and thus generating a feed-forward loop in relation to TFEB. Although high levels of nuclear TFEB are expected to enhance autophagy-lysosomal activity, undifferentiated mESC remarkably displayed low basal autophagy-lysosomal activity. Overexpression or knockout of TFEB did not affect the expression of TFEB lysosomal-autophagy target genes and TFEB also had a lesser binding affinity to its own lysosomal promoter-target genes in mESCs compared to differentiated cells. Collectively, these findings define a newly incorporative, moonlighting function for TFEB in regulating PTN, independent of its autophagy-lysosomal biogenesis roles.

Dataset Information

RSL24D1 sustains steady-state ribosome biogenesis and pluripotency translational programs in embryonic stem cells.

Publications

RSL24D1 sustains steady-state ribosome biogenesis and pluripotency translational programs in embryonic stem cells.

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