Journal
CELL STEM CELL
Volume 22, Issue 3, Pages 369-+Publisher
CELL PRESS
DOI: 10.1016/j.stem.2018.02.004
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Funding
- NIH [5P30CA082103, U01MH105028, 1F30HD093116, R01GM113014, R01GM123556]
- Diabetes Research Center (DRC) NIH grant [P30 DK063720]
- Biomedical Technology Research Centers Program of the NIH National Institute of General Medical Sciences [NIH NIGMS 8P41GM103481, NIH 1S10OD016229]
- UCSF Program for Breakthrough Biomedical Research (PBBR)
- Shurl and Kay Curci Foundation research grant
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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.
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