Identification of a novel gene signature of ES cells self-renewal fluctuation through system-wide analysis

PLoS One. 2014 Jan 2;9(1):e83235. doi: 10.1371/journal.pone.0083235. eCollection 2014.

Abstract

Embryonic Stem cells (ESCs) can be differentiated into ectoderm, endoderm, and mesoderm derivatives, producing the majority of cell types. In regular culture conditions, ESCs' self-renewal is maintained through molecules that inhibit spontaneous differentiation enabling long-term cellular expansion. This undifferentiating condition is characterized by multiple metastable states that fluctuate between self-renewal and differentiation balance. Here, we aim to characterize the high-pluripotent ESC metastate marked by the expression of Zscan4 through a supervised machine learning framework based on an ensemble of support vector machine (SVM) classifiers. Our study revealed a leukaemia inhibitor factor (Lif) dependent not-canonical pluripotency signature (AF067063, BC061212, Dub1, Eif1a, Gm12794, Gm13871, Gm4340, Gm4850, Tcstv1/3, and Zfp352), that specifically marks Zscan4 ESCs' fluctuation. This novel ESC metastate is enhanced by high-pluripotency culture conditions obtained through Extracellular signal Regulated-Kinase (ERK) and Glycogen synthase kinase-3 (Gsk-3) signaling inhibition (2i). Significantly, we reported that the conditional ablation of the novel ESC metastate marked by the expression of Gm12794 is required for ESCs self-renewal maintenance. In conclusion, we extend the comprehension of ESCs biology through the identification of a novel molecular signature associated to pluripotency programming.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Artificial Intelligence
  • Biomarkers
  • Cell Differentiation / genetics*
  • Cell Proliferation
  • Embryonic Stem Cells / cytology*
  • Embryonic Stem Cells / metabolism*
  • Gene Expression
  • Gene Expression Profiling*
  • Genes, Reporter
  • Mice
  • Transcription Factors / genetics
  • Transcriptome*

Substances

  • Biomarkers
  • Transcription Factors

Grants and funding

The study was funded by European International Reintegration Grant (number 239519), by Basic research investment fund (number RBFR10XCD3_002), and by IRGS Biogem Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.