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

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

Research output: Contribution to journalArticlepeer-review


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
Pages (from-to)2364
JournalNat. Commun.
Issue number1
Publication statusPublished - May 12 2020


  • Animals
  • Cell Line
  • Cell Self Renewal/genetics
  • Cellular Reprogramming/genetics
  • Embryonic Stem Cells
  • Enhancer Elements, Genetic/genetics
  • Gain of Function Mutation
  • Gene Expression Regulation/physiology
  • Gene Knockdown Techniques
  • Humans
  • Induced Pluripotent Stem Cells/physiology
  • Kruppel-Like Transcription Factors/genetics
  • Mice
  • Promoter Regions, Genetic/genetics
  • RNA, Small Interfering/metabolism
  • Smad3 Protein/metabolism
  • Transforming Growth Factor beta/metabolism
  • Zinc Fingers


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