Division of Organogenesis and Regeneration, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo 162-8655, Japan.
Mol Cell. 2020 Aug 20;79(4):660-676.e8. doi: 10.1016/j.molcel.2020.07.012. Epub 2020 Aug 4.
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.
特定转录因子（Hnf4α 加 Foxa1、Foxa2 或 Foxa3）的组合可以诱导小鼠成纤维细胞直接转化为肝细胞样细胞。然而，肝重编程的分子机制在很大程度上尚不清楚。在这里，我们表明 Foxa 蛋白家族成员和 Hnf4α 依次合作结合染色质以激活肝脏特异性基因表达。虽然所有 Foxa 蛋白都作为先驱因子结合并打开封闭染色质的区域，但 Foxa3 具有从靶基因转录起始位点的远端转移到近端区域、结合 RNA 聚合酶 II 并共同穿越靶基因的独特潜力。Foxa3 的这些独特特征对于在成纤维细胞中诱导肝命运是必不可少的。类似的转录因子与 RNA 聚合酶 II 的功能偶联可能发生在其他情况下，其中转录激活可以诱导细胞分化。
