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

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 HNF4 α , 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, HNF4 α and miRs-200a, b, c and -34a as epistatic elements controlling hepatic stem cell maintenance/differentiation.