title: Identification of a novel gene signature of ES cells self-renewal fluctuation through system-wide analysis.
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.
authors.affiliation: 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.
authors.forename: Luigi
authors.initials: L
authors.lastname: Cerulo
authors.affiliation: 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.
authors.forename: Daniela
authors.initials: D
authors.lastname: Tagliaferri
authors.affiliation: Department of Stem Cell and Development, Istituto di Ricerche Genetiche Gaetano Salvatore Biogem scarl, Ariano Irpino, Italy.
authors.forename: Pina
authors.initials: P
authors.lastname: Marotta
authors.affiliation: Department of Stem Cell and Development, Istituto di Ricerche Genetiche Gaetano Salvatore Biogem scarl, Ariano Irpino, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Zoppoli
authors.affiliation: Department of Stem Cell and Development, Istituto di Ricerche Genetiche Gaetano Salvatore Biogem scarl, Ariano Irpino, Italy.
authors.forename: Filomena
authors.initials: F
authors.lastname: Russo
authors.affiliation: Department of Stem Cell and Development, Istituto di Ricerche Genetiche Gaetano Salvatore Biogem scarl, Ariano Irpino, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Mazio
authors.affiliation: 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.
authors.forename: Mario
authors.initials: M
authors.lastname: DeFelice
authors.affiliation: 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.
authors.forename: Michele
authors.initials: M
authors.lastname: Ceccarelli
authors.affiliation: 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.
authors.forename: Geppino
authors.initials: G
authors.lastname: Falco
mesh_terms: D000818:Animals; D001185:Artificial Intelligence; D015415:Biomarkers; D002454:Cell Differentiation / Q000235:genetics*; D049109:Cell Proliferation; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D015870:Gene Expression; D020869:Gene Expression Profiling; D017930:Genes, Reporter; D051379:Mice; D014157:Transcription Factors / Q000235:genetics; D059467:Transcriptome
chemical_list: D015415:Biomarkers; D014157:Transcription Factors