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An epistatic mini-circuitry between the transcription factors Snail and HNF4α controls liver stem cell and hepatocyte features exhorting opposite regulation on stemness-inhibiting microRNAs

  • Autori: Garibaldi, F.; Cicchini, C.; Conigliaro, A.; Santangelo, L.; Cozzolino, A.; Grassi, G.; Marchetti, A.; Tripodi, M.; Amicone, L.
  • Anno di pubblicazione: 2012
  • Tipologia: Articolo in rivista (Articolo in rivista)
  • Parole Chiave: Hepatocyte differentiation; HNF4a; MiR-34a; MiRs-200; Snail; Stemness; Animals; Cell Differentiation; Epithelial-Mesenchymal Transition; Hepatocyte Nuclear Factor 4; Hepatocytes; Liver; Mice; Mice, Knockout; MicroRNAs; Snail Family Transcription Factors; Stem Cells; Transcription Factors; Transcription, Genetic; Cell Biology; Molecular Biology
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Preservation of the epithelial state involves the stable repression of epithelial-to-mesenchymal transition program, whereas maintenance of the stem compartment requires the inhibition of differentiation processes. A simple and direct molecular mini-circuitry between master elements of these biological processes might provide the best device to keep balanced such complex phenomena. In this work, we show that in hepatic stem cell Snail, a transcriptional repressor of the hepatocyte differentiation master gene HNF4α, directly represses the expression of the epithelial microRNAs (miRs)-200c and-34a, which in turn target several stem cell genes. Notably, in differentiated hepatocytes HNF4α, previously identified as a transcriptional repressor of Snail, induces the miRs-34a and-200a, b, c that, when silenced, causes epithelial dedifferentiation and reacquisition of stem traits. Altogether these data unveiled Snail, HNF4α and miRs-200a, b, c and-34a as epistatic elements controlling hepatic stem cell maintenance/differentiation. © 2012 Macmillan Publishers Limited. All rights reserved.