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‐ID(CONNECT) TFs also engage in reciprocal transcriptional regulation with TFs of the CoRC. In homeostatic basal conditions, this translates into Hep‐ID(CONNECT) TFs being involved in fine tuning CoRC TF expression including their rhythmic expression patterns. Moreover, a role for Hep‐ID(CONNECT) TFs in the control of hepatocyte identity is revealed in dedifferentiated hepatocytes where Hep‐ID(CONNECT) 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.