Specific combinations of two transcription factors (Hnf4α plus Foxa1, Foxa2, or Foxa3) can induce direct conversion of mouse fibroblasts into hepatocyte-like cells. However, the molecular mechanisms underlying hepatic reprogramming are largely unknown. Here, we show that the Foxa protein family members and Hnf4α sequentially and cooperatively bind to chromatin to activate liver-specific gene expression. Although all Foxa proteins bind to and open regions of closed chromatin as pioneer factors, Foxa3 has the unique potential of transferring from the distal to proximal regions of the transcription start site of target genes, binding RNA polymerase II, and co-traversing target genes. These distinctive characteristics of Foxa3 are essential for inducing the hepatic fate in fibroblasts. Similar functional coupling of transcription factors to RNA polymerase II may occur in other contexts whereby transcriptional activation can induce cell differentiation.

两种转录因子（Hnf4α加Foxa1，Foxa2或Foxa3）的特定组合可以诱导小鼠成纤维细胞直接转化为肝细胞样细胞。但是，肝脏重编程的分子机制在很大程度上尚不清楚。在这里，我们显示Foxa蛋白家族成员和Hnf4α顺序并协作地结合染色质以激活肝脏特异性基因表达。尽管所有Foxa蛋白都与封闭染色质的开放区域结合并形成开放区域，这是先驱因素，但Foxa3具有从靶基因转录起始位点的远端到近端区域转移，结合RNA聚合酶II和共同穿越靶基因的独特潜力。Foxa3的这些独特特征对于诱导成纤维细胞的肝脏命运至关重要。