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 () and Graziano Martello ()
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Irene Zorzan: University of Padua
Marco Pellegrini: University of Padua
Mattia Arboit: University of Padua
Danny Incarnato: University of Turin
Mara Maldotti: University of Turin
Mattia Forcato: University of Modena and Reggio Emilia
Guidantonio Malagoli Tagliazucchi: University of Modena and Reggio Emilia
Elena Carbognin: University of Padua
Marco Montagner: University of Padua
Salvatore Oliviero: University of Turin
Graziano Martello: University of Padua

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-16205-9

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