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Cell Rep. 2013 Dec 26;5(6):1611-24. doi: 10.1016/j.celrep.2013.11.021. Epub 2013 Dec 12.

Switch enhancers interpret TGF-β and Hippo signaling to control cell fate in human embryonic stem cells.

Author information

1
Center for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto M5G 1X5, Canada.
2
Center for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto M5S 1A8, Canada. Electronic address: wrana@lunenfeld.ca.

Abstract

A small toolkit of morphogens is used repeatedly to direct development, raising the question of how context dictates interpretation of the same cue. One example is the transforming growth factor β (TGF-β) pathway that in human embryonic stem cells fulfills two opposite functions: pluripotency maintenance and mesendoderm (ME) specification. Using proteomics coupled to analysis of genome occupancy, we uncover a regulatory complex composed of transcriptional effectors of the Hippo pathway (TAZ/YAP/TEAD), the TGF-β pathway (SMAD2/3), and the pluripotency regulator OCT4 (TSO). TSO collaborates with NuRD repressor complexes to buffer pluripotency gene expression while suppressing ME genes. Importantly, the SMAD DNA binding partner FOXH1, a major specifier of ME, is found near TSO elements, and upon fate specification we show that TSO is disrupted with subsequent SMAD-FOXH1 induction of ME. These studies define switch-enhancer elements and provide a framework to understand how cellular context dictates interpretation of the same morphogen signal in development.

PMID:
24332857
DOI:
10.1016/j.celrep.2013.11.021
[Indexed for MEDLINE]
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