The Dynamics of Transcriptional Activation by Hepatic Reprogramming Factors

• Published in: Molecular cell Vol. 79; no. 4; pp. 660 - 676.e8
• Main Authors: Horisawa, Kenichi, Udono, Miyako, Ueno, Kazuko, Ohkawa, Yasuyuki, Nagasaki, Masao, Sekiya, Sayaka, Suzuki, Atsushi
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 20.08.2020
• Subjects: cell proliferation; direct reprogramming; gene expression; hepatocyte; liver; pioneer factor; RNA polymerase II; transactivation domain; transcription factor; transcriptional activation; transcription factor; hepatocyte; cell proliferation; liver; direct reprogramming; transactivation domain; pioneer factor; RNA polymerase II; transcriptional activation; gene expression
• DOI: 10.1016/j.molcel.2020.07.012
• ISSN: 1097-2765

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. [Display omitted] •Foxa proteins and Hnf4α sequentially and cooperatively bind to chromatin in cells•Foxa3 transfers from the distal to proximal regions of transcription start sites•Foxa3 physically and functionally interacts with RNA polymerase II•Foxa3 travels together with RNA polymerase II to induce liver gene expression During the direct reprogramming of fibroblasts to hepatocyte-like cells, Foxa3 acts as a pioneer factor, similar to Foxa1 and Foxa2, but leaves its binding site to interact and migrate with RNA polymerase II, thereby inducing the transcription of target genes.