A Feedback Loop Between The Liver-Enriched Transcription Factor Network and Mir-122 Controls Hepatocyte Differentiation
- Authors
- Laudadio, I., Manfroid, I., Achouri, Y., Schmidt, D., Wilson, M.D., Cordi, S., Thorrez, L., Knoops, L., Jacquemin, P., Schuit, F., Pierreux, C.E., Odom, D.T., Peers, B., and Lemaigre, F.P.
- ID
- ZDB-PUB-110920-32
- Date
- 2012
- Source
- Gastroenterology 142(1): 119-29 (Journal)
- Registered Authors
- Manfroid, Isabelle, Peers, Bernard
- Keywords
- liver development, gene reguatory network, biliary hyperplasia, embryonic
- MeSH Terms
-
- Animals
- Base Sequence
- Binding Sites
- Cell Differentiation*
- Cells, Cultured
- Embryo Culture Techniques
- Feedback, Physiological
- Gene Expression Regulation, Developmental
- Hepatocyte Nuclear Factor 3-beta/genetics
- Hepatocyte Nuclear Factor 3-beta/metabolism
- Hepatocyte Nuclear Factor 6/genetics
- Hepatocyte Nuclear Factor 6/metabolism
- Hepatocytes/metabolism*
- Homeodomain Proteins/genetics
- Homeodomain Proteins/metabolism
- Mice
- Mice, Knockout
- Mice, Transgenic
- MicroRNAs/metabolism*
- Molecular Sequence Data
- Promoter Regions, Genetic
- RNA Interference
- Signal Transduction
- Transcription Factors/deficiency
- Transcription Factors/genetics
- Transcription Factors/metabolism*
- Transfection
- Zebrafish/embryology
- Zebrafish/genetics
- Zebrafish/metabolism
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- PubMed
- 21920465 Full text @ Gastroenterology
BACKGROUND & AIMS:
Hepatocyte differentiation is controlled by liver-enriched transcription factors (LETFs). We investigated whether LETFs control microRNA expression during development and whether this control is required for hepatocyte differentiation.
METHODS:
Using in vivo DNA binding assays, we identify miR-122 as a direct target of the LETF hepatocyte nuclear factor (HNF)6. The role and mechanisms of the HNF6-miR-122 gene cascade in hepatocyte differentiation were studied in vivo and in vitro by gain- and loss-function experiments, using developing mice and zebrafish as model organisms.
RESULTS:
HNF6 and its paralog Onecut2 are strong transcriptional stimulators of miR-122 expression. Specific levels of miR-122 were required for proper progression of hepatocyte differentiation; miR-122 stimulated the expression of hepatocyte-specific genes and most LETFs, including HNF6. This indicates that HNF6 and miR-122 form a positive-feedback loop. Stimulation of hepatocyte differentiation by miR-122 was lost in HNF6-null mice, revealing that a transcription factor can mediate microRNA function. All hepatocyte-specific genes whose expression was stimulated by miR-122 bound HNF6 in vivo, confirming their direct regulation by this factor.
CONCLUSIONS:
Hepatocyte differentiation is directed by a positive-feedback loop that includes a transcription factor (HNF6) and a microRNA (miR-122) that are specifically expressed in liver. These findings could lead to methods to induce differentiation of hepatocytes in vitro and improve our understanding of liver cell dedifferentiation in pathological conditions.