An extended transcription factor regulatory network controls hepatocyte identity

Abstract

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. image Hepatocyte identity is controlled by interconnected transcription factors (TFs) extending beyond the core regulatory TF network (CoRC). The extended network comprises thyroid hormone receptor beta whose activation resets CoRC TFs expression and hepatocyte identity in dedifferentiated hepatocytes. Hepatocyte identity TFs of the CoRC are tightly connected to a large set of non‐hepatocyte‐specific TFs that we call Hep‐IDCONNECT TFs Hep‐IDCONNECT TFs fine tune hepatocyte identity TF expression in homeostatic basal conditions In dedifferentiated hepatocytes, Hep‐IDCONNECT TFs can reset hepatocyte identity as shown for the thyroid hormone receptor beta whose activation induces expression of the CoRC TFs in hepatocarcinoma and in hepatocytes subjected to inflammation‐induced loss of identity.