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First published online October 26, 2006
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Submitted on July 12, 2006
Accepted on October 18, 2006

Embryonic Stem Cells

Analysis of OCT4 dependent transcriptional networks regulating self renewal and pluripotency in human embryonic stem cells

Yasmin Babaie 1, Ralf Herwig 2, Boris Greber 2, Thore C. Brink 2, Wasco Wruck 2, Detlef Groth 2, Hans Lehrach 2, Tom Burdon 1, James Adjaye 2*

1 Roslin Institute, Department of Gene Function and Development, Roslin, Midlothian, United Kingdom
2 Max Planck Institute for Molecular Genetics, Department of Vertebrate Genomics, Berlin, Germany

* To whom correspondence should be addressed. E-mail: adjaye{at}molgen.mpg.de.


  Abstract

The POU domain transcription factor OCT4 is a key regulator of pluripotency in the early mammalian embryo and is highly expressed in the inner cell mass of the blastocyst. Consistent with its essential role in maintaining pluripotency, Oct4 expression is rapidly down-regulated during formation of the trophoblast lineage. To enhance our understanding of the molecular basis of this differentiation event in humans, we used a functional genomics approach involving RNAi-mediated suppression of OCT4 function in a human embryonic stem (ES) cell line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of >1000 genes including targets regulated directly by OCT4 either positively (NANOG, SOX2, REX1, LEFTB, LEFTA/EBAF DPPA4, THY1 and TDGF1) or negatively (CDX2, EOMES, BMP4, TBX18, Brachyury (T), DKK1, HLX1, GATA6, ID2 and DLX5) as well as targets for the OCT4-associated stem cell regulators SOX2 and NANOG. Our data set includes regulators of ACTIVIN, BMP, FGF and WNT signaling. These pathways are implicated in regulating hES cell differentiation and therefore further validate the results of our analysis. In addition we identified a number of differentially expressed genes that are involved in epigenetics, chromatin remodelling, apoptosis and metabolism that may point to underlying molecular mechanisms that regulate pluripotency and trophoblast differentiation in humans. Significant concordance between this data set and previous comparisons between ICM and trophectoderm in human embryos indicates that the study of human ES cell differentiation in vitro represents a useful model of early embryonic differentiation in humans.

Key Words. Human embryonic stem cells, Inner Cell Mass, Trophoblast, Pluripotency, RNAi, OCT4, CDX2, Microarrays




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