Analysis of Oct4-dependent transcriptional networks regulating self-renewal and pluripotency in human embryonic stem cells

被引:273
作者
Babaie, Yasmin
Herwig, Ralf
Greber, Boris
Brink, Thore C.
Wruck, Wasco
Groth, Detlef
Lehrach, Hans
Burdon, Tom
Adjaye, James
机构
[1] Max Planck Inst Mol Genet, Dept Vertebrate Genom, D-14195 Berlin, Germany
[2] Roslin Inst, Dept Gene Funct & Dev, Roslin EH25 9PS, Midlothian, Scotland
基金
英国生物技术与生命科学研究理事会;
关键词
human embryonic stem cells; inner cell mass; trophoblast; pluripotency; RNA interference; OCT4; CDX2; microarrays;
D O I
10.1634/stemcells.2006-0426
中图分类号
Q813 [细胞工程];
学科分类号
摘要
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 downregulated 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 RNA interference-mediated suppression of OCT4 function in a human ESC line and analysis of the resulting transcriptional profiles to identify OCT4-dependent genes in human cells. We detected altered expression of > 1,000 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, fibroblast growth factor, and WNT signaling. These pathways are implicated in regulating human ESC 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 remodeling, 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 inner cell mass and trophectoderm in human embryos indicates that the study of human ESC differentiation in vitro represents a useful model of early embryonic differentiation in humans.
引用
收藏
页码:500 / 510
页数:11
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