Abstract
BackgroundUnderstanding the molecular mechanisms controlling pluripotency in embryonic stem cells (ESCs) is of central importance towards realizing their potentials in medicine and science. Cross-species examination of transcriptional co-expression allows elucidation of fundamental and species-specific mechanisms regulating ESC self-renewal or differentiation.Methodology/Principal FindingsWe examined transcriptional co-expression of ESCs from pathways to global networks under the framework of human-mouse comparisons. Using generalized singular value decomposition and comparative partition around medoids algorithms, evolutionarily conserved and divergent transcriptional co-expression regulating pluripotency were identified from ESC-critical pathways including ACTIVIN/NODAL, ATK/PTEN, BMP, CELL CYCLE, JAK/STAT, PI3K, TGFβ and WNT. A set of transcription factors, including FOX, GATA, MYB, NANOG, OCT, PAX, SOX and STAT, and the FGF response element were identified that represent key regulators underlying the transcriptional co-expression. By transcriptional intervention conducted in silico, dynamic behavior of pathways was examined, which demonstrate how much and in which specific ways each gene or gene combination effects the behavior transition of a pathway in response to ESC differentiation or pluripotency induction. The global co-expression networks of ESCs were dominated by highly connected hub genes such as IGF2, JARID2, LCK, MYCN, NASP, OCT4, ORC1L, PHC1 and RUVBL1, which are possibly critical in determining the fate of ESCs.Conclusions/SignificanceThrough these studies, evolutionary conservation at genomic, transcriptomic, and network levels is shown to be an effective predictor of molecular factors and mechanisms controlling ESC development. Various hypotheses regarding mechanisms controlling ESC development were generated, which could be further validated by in vitro experiments. Our findings shed light on the systems-level understanding of how ESC differentiation or pluripotency arises from the connectivity or networks of genes, and provide a “road-map” for further experimental investigation.
Highlights
Embryonic stem cells (ESCs) are pluripotent; they can replicate indefinitely and differentiate into multiple tissues from all three embryonic germ layers
The study suggests that the conserved OCT4/SOX2 synergistic action is an important activation mechanism in the FGF, LIF, NANOG and OCT4 directed pathways, which are regulated by a feedback loop formed by ESG1, FOXD3 and SOX2
The results suggest an essential role of JAK-mediated signaling through activating STAT2 and PI3K in embryonic stem cells (ESCs), while reaffirming different requirements of STAT3-mediated LIF signaling in mouse and human ESCs
Summary
Embryonic stem cells (ESCs) are pluripotent; they can replicate indefinitely and differentiate into multiple tissues from all three embryonic germ layers Due to their unique properties, ESCs serve as a model system for studying embryo development and hold great promise for regenerative medicine [1,2]. Transcription or growth factors such as GDF3, LEFTB, MYB, MYCN, NFYB, POLR3K, POU2F1, TDFG1 and UTF1 are conserved in the transcriptional response to ESC differentiation. These conserved pathways and factors may represent fundamental molecular mechanisms regulating ESC pluripotency. Cross-species examination of transcriptional coexpression allows elucidation of fundamental and species-specific mechanisms regulating ESC self-renewal or differentiation
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