title: 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.
abstract: 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.
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti, Department of Cellular Biotechnologies and Haematology, Sapienza University of Rome, Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Garibaldi
authors.forename: C
authors.initials: C
authors.lastname: Cicchini
authors.forename: A
authors.initials: A
authors.lastname: Conigliaro
authors.forename: L
authors.initials: L
authors.lastname: Santangelo
authors.forename: A M
authors.initials: AM
authors.lastname: Cozzolino
authors.forename: G
authors.initials: G
authors.lastname: Grassi
authors.forename: A
authors.initials: A
authors.lastname: Marchetti
authors.forename: M
authors.initials: M
authors.lastname: Tripodi
authors.forename: L
authors.initials: L
authors.lastname: Amicone
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D058750:Epithelial-Mesenchymal Transition; D051557:Hepatocyte Nuclear Factor 4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism*; D000071250:Snail Family Transcription Factors; D013234:Stem Cells / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D035683:MicroRNAs; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors