An epistatic mini-circuitry between the transcription factors Snail and HNF4 alpha controls liver stem cell and hepatocyte features exhorting opposite regulation on stemness-inhibiting microRNAs

作者：Garibaldi F; Cicchini C; Conigliaro A; Santangelo L; Cozzolino A M; Grassi G; Marchetti A; Tripodi M^*; Amicone L

来源：Cell Death and Differentiation, 2012, 19(6): 937-946.

DOI：10.1038/cdd.2011.175

• Snail
• HNF4 alpha
• miRs-200
• miR-34a
• stemness
• hepatocyte differentiation

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 minicircuitry 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 HNF4 alpha, 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 alpha, 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 alpha and miRs-200a, b, c and -34a as epistatic elements controlling hepatic stem cell maintenance/differentiation. Cell Death and Differentiation (2012) 19, 937-946; doi:10.1038/cdd.2011.175; published online 2 December 2011

• 出版日期2012-6