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

doi:10.1038/s41467-020-16205-9

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

Fondazione IRCCS Ca' Granda- Ospedale Maggiore Policlinico

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	2364
Journal	Nat. Commun.
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-16205-9
Publication status	Published - May 12 2020

Keywords

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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10.1038/s41467-020-16205-9

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

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.",

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author = "Irene Zorzan and Marco Pellegrini and Mattia Arboit and Danny Incarnato and Mara Maldotti and Mattia Forcato and Tagliazucchi, {Guidantonio Malagoli} and Elena Carbognin and Marco Montagner and Salvatore Oliviero and Graziano Martello",

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AU - Pellegrini, Marco

AU - Arboit, Mattia

AU - Incarnato, Danny

AU - Maldotti, Mara

AU - Forcato, Mattia

AU - Tagliazucchi, Guidantonio Malagoli

AU - Carbognin, Elena

AU - Montagner, Marco

AU - Oliviero, Salvatore

AU - Martello, Graziano

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AB - 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.

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

Abstract

Keywords

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