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

Zorzan, I., Pellegrini, M., Arboit, M., Incarnato, D., Maldotti, M., Forcato, M., Tagliazucchi, G. M., Carbognin, E., Montagner, M., Oliviero, S. & Martello, G., 1-Dec-2020, In : Nature Communications. 11, 1, 16 p., 2364.

Research output: Contribution to journalArticleAcademicpeer-review

  • Irene Zorzan
  • Marco Pellegrini
  • Mattia Arboit
  • Danny Incarnato
  • Mara Maldotti
  • Mattia Forcato
  • Guidantonio Malagoli Tagliazucchi
  • Elena Carbognin
  • Marco Montagner
  • Salvatore Oliviero
  • Graziano Martello

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.

Original languageEnglish
Article number2364
Number of pages16
JournalNature Communications
Volume11
Issue number1
Publication statusPublished - 1-Dec-2020

    Keywords

  • EMBRYONIC STEM-CELLS, MAINTAINS PLURIPOTENCY, DIFFERENTIATION, MOUSE, NAIVE, EXPRESSION, INDUCTION, NANOG, LINES, DERIVATION

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