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Highlights d Foxa proteins and Hnf4a sequentially and cooperatively bind to chromatin in cells d Foxa3 transfers from the distal to proximal regions of transcription start sites d Foxa3 physically and functionally interacts with RNA polymerase II d Foxa3 travels together with RNA polymerase II to induce liver gene expression

In liver development, hepatoblasts that act as hepatic stem/progenitor cells proliferate and differentiate into both hepatocytes and cholangiocytes to form liver tissues. Although numerous factors contribute to this event, little is known about the roles of microRNAs in hepatoblast proliferation and differentiation. In this study, we focused on the lineage-28 (Lin28) family proteins, which are required for microRNA regulation in pluripotent stem cells and cancer cells, and investigated their roles as regulatory factors for the properties of hepatoblasts. Conclusion: Lin28b was specifically expressed in hepatoblasts, and its suppression induced growth arrest and cholangiocyte differentiation of hepatoblasts; mechanistically, Lin28b positively regulates the expression of Lin28b itself and cell cycle-related proteins in hepatoblasts by suppressing the maturation of target microRNAs, lethal-7b and miR-125a/b, enabling maintenance of the stem cell properties of hepatoblasts, such as their capabilities for proliferation and bi-lineage differentiation, during liver development. (HEPATOLOGY 2016;64:245-260) M icroRNAs (miRNAs), which are composed of 20-25 nucleotides of RNA, bind to partial complementary sequences in the 3 0 -untranslated region (UTR) of their target transcripts, recruit RNA-induced silencing complex to inhibit the translation of these transcripts, and are involved in the regulation of many aspects of cellular function. (1)(2)(3)(4)(5)(6) Regarding the involvement of miRNAs in liver development, miR-122 is highly expressed in the liver after embryonic day (E) 11.5 and contributes to the progression of liver development by suppressing Cut-like homeobox 1 (also known as CCAAT displacement protein), which acts as a transcriptional repressor against terminal differentiation of hepatocytes. (7) It was also reported that miR-23b interferes with the differentiation of cholangiocytes through suppression of the transforming growth factor-b signaling pathway by targeting Smad3/4/5 in the liver of E16.5-E17.5 mouse embryos. (8) Moreover, miR-346 and miR-500 are highly expressed in the developing liver, and their expression gradually decreases in accordance with the progression of liver development. (9) Conversely, miR-30 is specifically expressed in cholangiocytes between E18.5 and neonatal stages and contributes to bile duct formation by targeting trinucleotide repeat containing 6a, which is a subunit of the RNA-induced silencing

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