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

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

Author information

1
Department of Stem Cell and Development, Istituto di Ricerche Genetiche Gaetano Salvatore Biogem scarl, Ariano Irpino, Italy ; Department of Science, Università degli Studi del Sannio, Benevento, Italy.
2
Department of Stem Cell and Development, Istituto di Ricerche Genetiche Gaetano Salvatore Biogem scarl, Ariano Irpino, Italy.
3
Department of Stem Cell and Development, Istituto di Ricerche Genetiche Gaetano Salvatore Biogem scarl, Ariano Irpino, Italy ; Department of Medicina Molecolare e Biotecnologie mediche, Università di Napoli Federico II, Naples, Italy.

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.

PMID:
24392082
PMCID:
PMC3879232
DOI:
10.1371/journal.pone.0083235
[Indexed for MEDLINE]
Free PMC Article

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