Feedback Loop Between The Liver-Enriched Transcription Factor Network and Mir-122 Controls Hepatocyte Differentiation.

in Gastroenterology (2011)

Hepatocyte differentiation is controlled by a network of liver-enriched transcription factors (LETFs). Here we investigated whether LETFs control microRNA expression during development, and whether such ... [more ▼]

Hepatocyte differentiation is controlled by a network of liver-enriched transcription factors (LETFs). Here we investigated whether LETFs control microRNA expression during development, and whether such control is required for hepatocyte differentiation. Methods. Using in vivo DNA-binding assays we identified miR-122 as a direct target of the LETF Hepatocyte Nuclear Factor (HNF) 6. The role and mechanism of the HNF6 - miR-122 gene cascade in hepatocyte differentiation was studied in vivo and in vitro by gain- and loss-function experiments using the developing mouse and zebrafish as model organisms. Results. HNF6 and its paralog Onecut2 are potent transcriptional stimulators of miR-122 expression during liver development. Conversely, accurate levels of miR-122 are required to ensure proper progression of hepatocyte differentiation. MiR-122 exerts this function by stimulating the expression of hepatocyte-specific genes and of most LETFs, including HNF6. This reveals the existence of a HNF6 – miR-122 positive feedback loop. Moreover, stimulation of hepatocyte differentiation by miR-122 is abolished in an HNF6-null background, revealing that a transcription factor can mediate microRNA function. Confirming direct regulation, all hepatocyte-specific genes whose expression is stimulated by miR-122 are occupied in vivo by HNF6. Conclusions. Our findings reveal a novel control of hepatocyte differentiation, which is directed by a positive feedback loop between a transcription factor and a microRNA, both being specifically expressed in liver. This work also bears significance for in vitro programmed differentiation of hepatocytes and for understanding dedifferentiation in pathological conditions. [less ▲]