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Cell Stem Cell. 2018 Mar 1;22(3):369-383.e8. doi: 10.1016/j.stem.2018.02.004.

The Transcriptionally Permissive Chromatin State of Embryonic Stem Cells Is Acutely Tuned to Translational Output.

Author information

1
Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Center for Reproductive Sciences and Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA.
2
Department of Pharmaceutical Chemistry, Mass Spectrometry Facility, School of Pharmacy, University of California, San Francisco, San Francisco, CA 94158, USA.
3
UCSF Diabetes Center, WM Keck Center for Noncoding RNAs, Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA.
4
Department of Neurological Surgery, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA.
5
Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Center for Reproductive Sciences and Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: mrsantos@lunenfeld.ca.

Abstract

A permissive chromatin environment coupled to hypertranscription drives the rapid proliferation of embryonic stem cells (ESCs) and peri-implantation embryos. We carried out a genome-wide screen to systematically dissect the regulation of the euchromatic state of ESCs. The results revealed that cellular growth pathways, most prominently translation, perpetuate the euchromatic state and hypertranscription of ESCs. Acute inhibition of translation rapidly depletes euchromatic marks in mouse ESCs and blastocysts, concurrent with delocalization of RNA polymerase II and reduction in nascent transcription. Translation inhibition promotes rewiring of chromatin accessibility, which decreases at a subset of active developmental enhancers and increases at histone genes and transposable elements. Proteome-scale analyses revealed that several euchromatin regulators are unstable proteins and continuously depend on a high translational output. We propose that this mechanistic interdependence of euchromatin, transcription, and translation sets the pace of proliferation at peri-implantation and may be employed by other stem/progenitor cells.

KEYWORDS:

Chd1; blastocyst; embryonic stem cells; euchromatin; hypertranscription; mTOR; permissive chromatin; ribosome; translation

PMID:
29499153
PMCID:
PMC5836508
[Available on 2019-03-01]
DOI:
10.1016/j.stem.2018.02.004

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