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

Cell Death Differ. 2012 Jun;19(6):937-46. doi: 10.1038/cdd.2011.175. Epub 2011 Dec 2.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Epithelial-Mesenchymal Transition
  • Hepatocyte Nuclear Factor 4 / deficiency
  • Hepatocyte Nuclear Factor 4 / genetics
  • Hepatocyte Nuclear Factor 4 / metabolism*
  • Hepatocytes / metabolism*
  • Liver / cytology
  • Liver / metabolism
  • Mice
  • Mice, Knockout
  • MicroRNAs / metabolism*
  • Snail Family Transcription Factors
  • Stem Cells / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic

Substances

  • HNF4A protein, human
  • Hepatocyte Nuclear Factor 4
  • MicroRNAs
  • Snail Family Transcription Factors
  • Transcription Factors