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The transcriptional regulator ZNF398 mediates pluripotency and epithelial character downstream of TGF-beta in human PSCs

Author

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  • Irene Zorzan

    (University of Padua)

  • Marco Pellegrini

    (University of Padua
    Stem Cells and Regenerative Medicine)

  • Mattia Arboit

    (University of Padua)

  • Danny Incarnato

    (University of Turin
    Italian Institute for Genomic Medicine (IIGM)
    University of Groningen)

  • Mara Maldotti

    (University of Turin
    Italian Institute for Genomic Medicine (IIGM))

  • Mattia Forcato

    (University of Modena and Reggio Emilia)

  • Guidantonio Malagoli Tagliazucchi

    (University of Modena and Reggio Emilia
    University College London)

  • Elena Carbognin

    (University of Padua)

  • Marco Montagner

    (University of Padua)

  • Salvatore Oliviero

    (University of Turin
    Italian Institute for Genomic Medicine (IIGM))

  • Graziano Martello

    (University of Padua)

Abstract

Human pluripotent stem cells (hPSCs) have the capacity to give rise to all differentiated cells of the adult. TGF-beta is used routinely for expansion of conventional hPSCs as flat epithelial colonies expressing the transcription factors POU5F1/OCT4, NANOG, SOX2. Here we report a global analysis of the transcriptional programme controlled by TGF-beta followed by an unbiased gain-of-function screening in multiple hPSC lines to identify factors mediating TGF-beta activity. We identify a quartet of transcriptional regulators promoting hPSC self-renewal including ZNF398, a human-specific mediator of pluripotency and epithelial character in hPSCs. Mechanistically, ZNF398 binds active promoters and enhancers together with SMAD3 and the histone acetyltransferase EP300, enabling transcription of TGF-beta targets. In the context of somatic cell reprogramming, inhibition of ZNF398 abolishes activation of pluripotency and epithelial genes and colony formation. Our findings have clear implications for the generation of bona fide hPSCs for regenerative medicine.

Suggested Citation

  • Irene Zorzan & Marco Pellegrini & Mattia Arboit & Danny Incarnato & Mara Maldotti & Mattia Forcato & Guidantonio Malagoli Tagliazucchi & Elena Carbognin & Marco Montagner & Salvatore Oliviero & Grazia, 2020. "The transcriptional regulator ZNF398 mediates pluripotency and epithelial character downstream of TGF-beta in human PSCs," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16205-9
    DOI: 10.1038/s41467-020-16205-9
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    Cited by:

    1. Giorgia Maria Ferlazzo & Anna Maria Gambetta & Sonia Amato & Noemi Cannizzaro & Silvia Angiolillo & Mattia Arboit & Linda Diamante & Elena Carbognin & Patrizia Romani & Federico La Torre & Elena Galim, 2023. "Genome-wide screening in pluripotent cells identifies Mtf1 as a suppressor of mutant huntingtin toxicity," Nature Communications, Nature, vol. 14(1), pages 1-24, December.

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