The Dynamics of Transcriptional Activation by Hepatic Reprogramming Factors

Mol Cell. 2020 Aug 20;79(4):660-676.e8. doi: 10.1016/j.molcel.2020.07.012. Epub 2020 Aug 4.

Abstract

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.

Keywords: RNA polymerase II; cell proliferation; direct reprogramming; gene expression; hepatocyte; liver; pioneer factor; transactivation domain; transcription factor; transcriptional activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Cells, Cultured
  • Cellular Reprogramming / physiology
  • Chromatin / metabolism
  • DNA Polymerase II / genetics
  • DNA Polymerase II / metabolism
  • Fibroblasts / cytology
  • Fibroblasts / physiology
  • Gene Expression Regulation
  • Hepatocyte Nuclear Factor 3-gamma / genetics
  • Hepatocyte Nuclear Factor 3-gamma / metabolism*
  • Hepatocyte Nuclear Factor 4 / genetics
  • Hepatocyte Nuclear Factor 4 / metabolism*
  • Liver / cytology*
  • Liver / physiology*
  • Mice, Inbred C57BL
  • Protein Domains
  • Transcription Initiation Site
  • Transcriptional Activation*

Substances

  • Chromatin
  • Foxa3 protein, mouse
  • Hepatocyte Nuclear Factor 4
  • Hnf4a protein, mouse
  • Hepatocyte Nuclear Factor 3-gamma
  • DNA Polymerase II