Control of early fate decisions in human ES cells by distinct states of TGFbeta pathway activity.
The mechanisms controlling self-renewal versus lineage commitment in human embryonic stem (hES) cells are not well understood. Nonetheless, current knowledge suggests a crucial role for TGFbeta signaling in controlling these early fate decisions. We have investigated the effects of TGFbeta pathway activation and inhibition on gene expression in hES cells. Our data reveal that SMAD 2/3 signaling directly supports NANOG expression, while SMAD 1/5/8 activation moderately represses SOX2. In addition, genes encoding key developmentally relevant signaling molecules and transcription factors appear to be immediately downstream of SMAD 1/5/8 signaling, or require both SMAD 1/5/8 and 2/3 activation, or inactivation of TGFbeta signaling for their induction. Defined stimulation/inhibition of the two TGFbeta branches appeared to control early fate decisions in accordance with these downstream transcriptional effects. Our results therefore help to better understand how pluripotency is mediated at the transcriptional level.
Greber
Boris
B
Max Planck Institute for Molecular Genetics, Department of Vertebrate Genomics, Berlin, Germany. boris.greber@mpi-muenster.mpg.de
Lehrach
Hans
H
Adjaye
James
J
D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D000071317:Nanog Homeobox Protein; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D051785:Smad Proteins / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D018398:Homeodomain Proteins; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D051785:Smad Proteins; D016212:Transforming Growth Factor beta