Cell Stem Cell
Volume 22, Issue 4, 5 April 2018, Pages 543-558.e12
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Article
Coordinated Control of mRNA and rRNA Processing Controls Embryonic Stem Cell Pluripotency and Differentiation

https://doi.org/10.1016/j.stem.2018.03.002Get rights and content
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Highlights

  • HTATSF1 specifically controls splicing and intron retention in ribosomal proteins

  • HTATSF1 regulates ribosomal RNA transcription and processing

  • HTATSF1 is required for efficient protein synthesis

  • HTATSF1-dependent protein synthesis controls pluripotency and differentiation

Summary

Stem cell-specific transcriptional networks are well known to control pluripotency, but constitutive cellular processes such as mRNA splicing and protein synthesis can add complex layers of regulation with poorly understood effects on cell-fate decisions. Here, we show that the RNA binding protein HTATSF1 controls embryonic stem cell differentiation by regulating multiple aspects of RNA processing during ribosome biogenesis. HTATSF1, in a complex with splicing factor SF3B1, controls intron removal from ribosomal protein transcripts and regulates ribosomal RNA transcription and processing, thereby controlling 60S ribosomal abundance and protein synthesis. HTATSF1-dependent protein synthesis is essential for naive pre-implantation epiblast to transition into post-implantation epiblast, a stage with transiently low protein synthesis, and further differentiation toward neuroectoderm. Together, these results identify coordinated regulation of ribosomal RNA and protein synthesis by HTATSF1 and show that this essential mechanism controls protein synthesis during early mammalian embryogenesis.

Keywords

stem cells
protein synthesis
intron retention
pluripotency
naïve pluripotency
neuroectoderm differentiation
splicing
RNA processing

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