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

• DOI: 10.1016/j.stem.2018.02.004
• Publication Date: 2018-03-01T16:57:53Z
• Authors: Aydan Bulut-Karsl...; Trisha A. Macrae; Juan A. Oses-Prieto; Sergio Covarrubias; Michelle Percharde; Gregory Ku; Aaron Diaz; Michael T. McManus; Alma L. Burlingame; Miguel Ramalho-Sa...
• Keywords: Male; 570; Biomedical and clinical sciences; Enhancer Elements; 1.1 Normal biological development and functioning; Stem Cell Research - Embryonic - Non-Human; translation; Medical and Health Sciences; Models, Biological; Euchromatin; Proto-Oncogene Proteins c-myc; Mice; Genetic; Models; Genetics; Animals; euchromatin; Stem Cell Research - Embryonic - Human; Embryonic Stem Cells; permissive chromatin; Genome; blastocyst; Protein Stability; TOR Serine-Threonine Kinases; Human Genome; Nuclear Proteins; Chd1; Cell Differentiation; hypertranscription; Biological Sciences; embryonic stem cells; Stem Cell Research; Biological; Chromatin; Histone Code; Biological sciences; Blastocyst; Enhancer Elements, Genetic; ribosome; Protein Biosynthesis; mTOR; DNA Transposable Elements; Female; RNA Interference; Biochemistry and Cell Biology; Generic health relevance; Transcription; Developmental Biology

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.