An extended transcription factor regulatory network controls hepatocyte identity

Cell identity is specified by a core transcriptional regulatory circuitry (CoRC), typically limited to a small set of interconnected cell-specific transcription factors (TFs). By mining global hepatic TF regulons, we reveal a more complex organization of the transcriptional regulatory network controlling hepatocyte identity. We show that tight functional interconnections controlling hepatocyte identity extend to non-cell-specific TFs beyond the CoRC, which we call hepatocyte identity (Hep-ID)(CONNECT) TFs. Besides controlling identity effector genes, Hep-IDCONNECT TFs also engage in reciprocal transcriptional regulation with TFs of the CoRC. In homeostatic basal conditions, this translates into Hep-IDCONNECT TFs being involved in fine tuning CoRC TF expression including their rhythmic expression patterns. Moreover, a role for Hep-IDCONNECT TFs in the control of hepatocyte identity is revealed in dedifferentiated hepatocytes where Hep-IDCONNECT TFs are able to reset CoRC TF expression. This is observed upon activation of NR1H3 or THRB in hepatocarcinoma or in hepatocytes subjected to inflammation-induced loss of identity. Our study establishes that hepatocyte identity is controlled by an extended array of TFs beyond the CoRC.

Automated summary

Cell identity is controlled by a core transcriptional regulatory circuitry (CoRC) consisting of cell-specific transcription factors (TFs). However, our study reveals that the transcriptional regulatory network regulating hepatocyte identity is more complex than initially thought. We identified a set of TFs, which we call hepatocyte identity (Hep-ID)(CONNECT) TFs, that not only control hepatocyte identity effector genes, but also interact with TFs of the CoRC. Furthermore, we found that Hep-IDCONNECT TFs play a role in fine-tuning CoRC TF expression and can reset CoRC TF expression in dedifferentiated hepatocytes.