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

Tobias A Beyer; Alexander Weiss; Yuliya Khomchuk; Kui Huang; Abiodun A Ogunjimi; Xaralabos Varelas; Jeffrey L Wrana

doi:10.1016/j.celrep.2013.11.021

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

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

Authors

Tobias A Beyer¹, Alexander Weiss¹, Yuliya Khomchuk¹, Kui Huang¹, Abiodun A Ogunjimi¹, Xaralabos Varelas¹, Jeffrey L Wrana²

Affiliations

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.

PMID: 24332857
DOI: 10.1016/j.celrep.2013.11.021

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acyltransferases
Cell Differentiation*
Embryonic Stem Cells / cytology
Embryonic Stem Cells / metabolism*
Forkhead Transcription Factors / genetics
Forkhead Transcription Factors / metabolism
Gene Expression Regulation, Developmental
Germ Layers / cytology
Germ Layers / metabolism
Hippo Signaling Pathway
Humans
Octamer Transcription Factor-3 / genetics
Octamer Transcription Factor-3 / metabolism
Pluripotent Stem Cells / cytology
Pluripotent Stem Cells / metabolism*
Protein Binding
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism*
Signal Transduction
Smad2 Protein / genetics
Smad2 Protein / metabolism*
Smad3 Protein / genetics
Smad3 Protein / metabolism*
Transcription Factors / genetics
Transcription Factors / metabolism
Transcription, Genetic
Transforming Growth Factor beta / genetics
Transforming Growth Factor beta / metabolism*

Substances

FOXH1 protein, human
Forkhead Transcription Factors
Octamer Transcription Factor-3
POU5F1 protein, human
SMAD2 protein, human
SMAD3 protein, human
Smad2 Protein
Smad3 Protein
Transcription Factors
Transforming Growth Factor beta
Acyltransferases
TAFAZZIN protein, human
Protein Serine-Threonine Kinases

Associated data

GEO/GSE52440

Grants and funding

106672/Canadian Institutes of Health Research/Canada