title: Three LIF-dependent signatures and gene clusters with atypical expression profiles, identified by transcriptome studies in mouse ES cells and early derivatives.
abstract: BACKGROUND
  Mouse embryonic stem (ES) cells remain pluripotent in vitro when grown in the presence of the cytokine Leukaemia Inhibitory Factor (LIF). Identification of LIF targets and of genes regulating the transition between pluripotent and early differentiated cells is a critical step for understanding the control of ES cell pluripotency.
  
  
  RESULTS
  By gene profiling studies carried out with mRNAs from ES cells and their early derivatives treated or not with LIF, we have identified i) LIF-dependent genes, highly expressed in pluripotent cells, whose expression level decreases sharply upon LIF withdrawal [Pluri genes], ii) LIF induced genes [Lifind genes] whose expression is differentially regulated depending upon cell context and iii) genes specific to the reversible or irreversible committed states. In addition, by hierarchical gene clustering, we have identified, among eight independent gene clusters, two atypical groups of genes, whose expression level was highly modulated in committed cells only. Computer based analyses led to the characterization of different sub-types of Pluri and Lifind genes, and revealed their differential modulation by Oct4 or Nanog master genes. Individual knock down of a selection of Pluri and Lifind genes leads to weak changes in the expression of early differentiation markers, in cell growth conditions in which these master genes are still expressed.
  
  
  CONCLUSIONS
  We have identified different sets of LIF-regulated genes depending upon the cell state (reversible or irreversible commitment), which allowed us to present a novel global view of LIF responses. We are also reporting on the identification of genes whose expression is strictly regulated during the commitment step. Furthermore, our studies identify sub-networks of genes with a restricted expression in pluripotent ES cells, whose down regulation occurs while the master knot (composed of OCT4, SOX2 and NANOG) is still expressed and which might be down-regulated together for driving cells towards differentiation.
authors.affiliation: Université Bordeaux, Bordeaux, France.
authors.forename: Marina
authors.initials: M
authors.lastname: Trouillas
authors.forename: Claire
authors.initials: C
authors.lastname: Saucourt
authors.forename: Bertrand
authors.initials: B
authors.lastname: Guillotin
authors.forename: Xavier
authors.initials: X
authors.lastname: Gauthereau
authors.forename: Li
authors.initials: L
authors.lastname: Ding
authors.forename: Frank
authors.initials: F
authors.lastname: Buchholz
authors.forename: Michael Xavier
authors.initials: MX
authors.lastname: Doss
authors.forename: Agapios
authors.initials: A
authors.lastname: Sachinidis
authors.forename: Jurgen
authors.initials: J
authors.lastname: Hescheler
authors.forename: Oliver
authors.initials: O
authors.lastname: Hummel
authors.forename: Norbert
authors.initials: N
authors.lastname: Huebner
authors.forename: Raivo
authors.initials: R
authors.lastname: Kolde
authors.forename: Jaak
authors.initials: J
authors.lastname: Vilo
authors.forename: Herbert
authors.initials: H
authors.lastname: Schulz
authors.forename: Hélène
authors.initials: H
authors.lastname: Boeuf
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D016000:Cluster Analysis; D053595:Embryonic Stem Cells / Q000378:metabolism*; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D053605:Leukemia Inhibitory Factor / Q000378:metabolism*; D051379:Mice / Q000235:genetics*; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D039904:Pluripotent Stem Cells / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; D053605:Leukemia Inhibitory Factor; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse