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Open Access Highly Accessed Research article

An integrated analysis of the SOX2 microRNA response program in human pluripotent and nullipotent stem cell lines

Sebastian F Vencken12*, Praveen Sethupathy3, Gordon Blackshields12, Cathy Spillane12, Salah Elbaruni12, Orla Sheils12, Michael F Gallagher12* and John J O’Leary12

Author Affiliations

1 Department of Histopathology, Trinity College Dublin, Sir Patrick Dun Research Laboratory, St. James’s Hospital, Dublin, Ireland

2 The Coombe Women and Infants University Hospital, Dublin, Ireland

3 Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

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BMC Genomics 2014, 15:711  doi:10.1186/1471-2164-15-711

Published: 25 August 2014

Abstract

Background

SOX2 is a core component of the transcriptional network responsible for maintaining embryonal carcinoma cells (ECCs) in a pluripotent, undifferentiated state of self-renewal. As such, SOX2 is an oncogenic transcription factor and crucial cancer stem cell (CSC) biomarker in embryonal carcinoma and, as more recently found, in the stem-like cancer cell component of many other malignancies. SOX2 is furthermore a crucial factor in the maintenance of adult stem cell phenotypes and has additional roles in cell fate determination. The SOX2-linked microRNA (miRNA) transcriptome and regulome has not yet been fully defined in human pluripotent cells or CSCs. To improve our understanding of the SOX2-linked miRNA regulatory network as a contribution to the phenotype of these cell types, we used high-throughput differential miRNA and gene expression analysis combined with existing genome-wide SOX2 chromatin immunoprecipitation (ChIP) data to map the SOX2 miRNA transcriptome in two human embryonal carcinoma cell (hECC) lines.

Results

Whole-microRNAome and genome analysis of SOX2-silenced hECCs revealed many miRNAs regulated by SOX2, including several with highly characterised functions in both cancer and embryonic stem cell (ESC) biology. We subsequently performed genome-wide differential expression analysis and applied a Monte Carlo simulation algorithm and target prediction to identify a SOX2-linked miRNA regulome, which was strongly enriched with epithelial-to-mesenchymal transition (EMT) markers. Additionally, several deregulated miRNAs important to EMT processes had SOX2 binding sites in their promoter regions.

Conclusion

In ESC-like CSCs, SOX2 regulates a large miRNA network that regulates and interlinks the expression of crucial genes involved in EMT.

Keywords:
SOX2; microRNA; Embryonic stem cell; Embryonal carcinoma; Pluripotency; EMT