Genomic chart guiding embryonic stem cell cardiopoiesis

Randolph S Faustino¹ , Atta Behfar¹ , Carmen Perez-Terzic¹^,2 and Andre Terzic¹

¹Marriott Heart Disease Research Program, Division of Cardiovascular Diseases, Departments of Medicine, Molecular Pharmacology and Experimental Therapeutics, and Medical Genetics, Mayo Clinic, First Street SW, Rochester, Minnesota 55905, USA

²Department of Physical Medicine and Rehabilitation, Mayo Clinic, First Street SW, Rochester, Minnesota 55905, USA

author email corresponding author email

Genome Biology 2008, 9:R6doi:10.1186/gb-2008-9-1-r6


Published:	9 January 2008

Subject areas: Cell biology, Development

Abstract

Background

Embryonic stem cells possess a pluripotent transcriptional background with the developmental capacity for distinct cell fates. Simultaneous expression of genetic elements for multiple outcomes obscures cascades relevant to specific cell phenotypes. To map molecular patterns critical to cardiogenesis, we interrogated gene expression in stem cells undergoing guided differentiation, and defined a genomic paradigm responsible for confinement of pluripotency.

Results

Functional annotation analysis of the transcriptome of differentiating embryonic stem cells exposed downregulated components of DNA replication, recombination and repair machinery, cell cycling, cancer mechanisms, and RNA post-translational modifications. Concomitantly, cardiovascular development, cell-to-cell signaling, cell development and cell movement were upregulated. These simultaneous gene ontology rearrangements engaged a repertoire switch that specified lineage development. Bioinformatic integration of genomic and gene ontology data further unmasked canonical signaling cascades prioritized within discrete phases of cardiopoiesis. Examination of gene relationships revealed a non-stochastic network anchored by integrin, WNT/β-catenin, transforming growth factor β and vascular endothelial growth factor pathways, validated by manipulation of selected cascades that promoted or restrained cardiogenic yield. Moreover, candidate genes within anchor pathways acted as nodes that organized correlated expression profiles into functional clusters, which collectively orchestrated and secured an overall cardiogenic theme.

Conclusion

The present systems biology approach reveals a dynamically integrated and tractable gene network fundamental to embryonic stem cell specification, and represents an initial step towards resolution of a genomic cardiopoietic atlas.