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    • An Extended Transcription Factor Regulatory Network Controls Hepatocyte Identity.

    Julie Dubois-Chevalier,Celine Gheeraert,Alexandre Berthier,Clemence Boulet,Vanessa Dubois,Loic Guille, Marie Fourcot,Guillemette Marot,Karine Gauthier,Laurent Dubuquoy,Bart Staels,Philippe Lefebvre,Jerome Eeckhoute

    EMBO REPORTS（2023）

    Univ Lille

    Cited 2|Views28
    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-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.
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    Key words
    cell identity,core regulatory network,hepatocyte dedifferentiation,liver disease,transcription factors
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