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Control of early fate decisions in human ES cells by distinct states of TGFβ pathway activity

MPS-Authors

Greber,  Boris
Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons50409

Lehrach,  Hans
Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons50054

Adjaye,  James
Molecular Embryology and Aging (James Adjaye), Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Citation

Greber, B., Lehrach, H., & Adjaye, J. (2008). Control of early fate decisions in human ES cells by distinct states of TGFβ pathway activity. Stem Cells and Development, 17(6), 1065-1077. doi:10.1089/scd.2008.0035.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0010-7E9C-F
Abstract
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 TGFβ signaling in controlling these early fate decisions. We have investigated the effects of TGFβ 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 TGFβ signaling for their induction. Defined stimulation/inhibition of the two TGFβ 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.