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

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

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
12 05 2020
Historique:
received: 12 09 2019
accepted: 17 04 2020
entrez: 14 5 2020
pubmed: 14 5 2020
medline: 1 9 2020
Statut: epublish

Résumé

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.

Identifiants

DOI: 10.1038/s41467-020-16205-9 PMID: 32398665 PMC: PMC7217929
pubmed: 32398665
doi: 10.1038/s41467-020-16205-9
pii: 10.1038/s41467-020-16205-9
pmc: PMC7217929
doi:

Substances chimiques

Kruppel-Like Transcription Factors 0
RNA, Small Interfering 0
SMAD3 protein, human 0
Smad3 Protein 0
Transforming Growth Factor beta 0
ZNF398 protein, human 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

2364

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Auteurs

Irene Zorzan (I)

Department of Molecular Medicine, Medical School, University of Padua, 35121, Padua, Italy.
ORCID: 0000-0002-9229-5293

Marco Pellegrini (M)

Department of Molecular Medicine, Medical School, University of Padua, 35121, Padua, Italy.
UCL Great Ormond Street Institute of Child Health, Developmental Biology and Cancer, Stem Cells and Regenerative Medicine, 30 Guilford Street, WC1N 1EH, London, UK.
ORCID: 0000-0002-3724-6640

Mattia Arboit (M)

Department of Molecular Medicine, Medical School, University of Padua, 35121, Padua, Italy.

Danny Incarnato (D)

Department of Life Sciences and Systems Biology and Molecular Biotechnology Center (MCB), University of Turin, 10126, Turin, Italy.
Italian Institute for Genomic Medicine (IIGM), 10060, Candiolo (TO), Italy.
Department of Molecular Genetics, Groningen Biomolecular Sciences and Biotechnology Institute (GBB), University of Groningen, Nijenborgh 7, 9747 AG, Groningen, the Netherlands.

Mara Maldotti (M)

Department of Life Sciences and Systems Biology and Molecular Biotechnology Center (MCB), University of Turin, 10126, Turin, Italy.
Italian Institute for Genomic Medicine (IIGM), 10060, Candiolo (TO), Italy.

Mattia Forcato (M)

Department of Life Sciences, University of Modena and Reggio Emilia, 41125, Modena, Italy.

Guidantonio Malagoli Tagliazucchi (GM)

Department of Life Sciences, University of Modena and Reggio Emilia, 41125, Modena, Italy.
UCL Genetics Institute, Department of Genetics, Evolution and Environment, University College London, Darwin Building, WC1E 6BT, London, UK.

Elena Carbognin (E)

Department of Molecular Medicine, Medical School, University of Padua, 35121, Padua, Italy.
ORCID: 0000-0001-6591-6915

Marco Montagner (M)

Department of Molecular Medicine, Medical School, University of Padua, 35121, Padua, Italy.
ORCID: 0000-0003-3080-2138

Salvatore Oliviero (S)

Department of Life Sciences and Systems Biology and Molecular Biotechnology Center (MCB), University of Turin, 10126, Turin, Italy. salvatore.oliviero@unito.it.
Italian Institute for Genomic Medicine (IIGM), 10060, Candiolo (TO), Italy. salvatore.oliviero@unito.it.
ORCID: 0000-0002-3405-765X

Graziano Martello (G)

Department of Molecular Medicine, Medical School, University of Padua, 35121, Padua, Italy. graziano.martello@unipd.it.
ORCID: 0000-0001-5520-085X

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › The transcriptional regulator ZNF398 mediates...
questionsmedicales.fr › Cellules › Cellules cultivées › Lignée cellulaire › The transcriptional regulator ZNF398 mediates...
questionsmedicales.fr › Phénomènes physiologiques › Croissance et développement › Croissance › Processus de croissance cellulaire › Prolifération cellulaire › Division cellulaire › Auto-renouvellement cellulaire › The transcriptional regulator ZNF398 mediates...
questionsmedicales.fr › Phénomènes génétiques › Reprogrammation cellulaire › The transcriptional regulator ZNF398 mediates...
questionsmedicales.fr › Cellules › Cellules souches › Cellules souches pluripotentes › Cellules souches embryonnaires › The transcriptional regulator ZNF398 mediates...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Gènes › Composants de gène › Éléments de régulation transcriptionnelle › Éléments activateurs (génétique) › The transcriptional regulator ZNF398 mediates...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Mutation gain de fonction › The transcriptional regulator ZNF398 mediates...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › The transcriptional regulator ZNF398 mediates...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Ciblage de gène › Techniques de knock-down de gènes › The transcriptional regulator ZNF398 mediates...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › The transcriptional regulator ZNF398 mediates...
questionsmedicales.fr › Cellules › Cellules souches › Cellules souches pluripotentes › Cellules souches pluripotentes induites › The transcriptional regulator ZNF398 mediates...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Facteurs de transcription Krüppel-like › The transcriptional regulator ZNF398 mediates...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › The transcriptional regulator ZNF398 mediates...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Gènes › Composants de gène › Éléments de régulation transcriptionnelle › Régions promotrices (génétique) › The transcriptional regulator ZNF398 mediates...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Acides nucléiques › ARN › ARN non traduit › Petit ARN non traduit › Petit ARN interférent › The transcriptional regulator ZNF398 mediates...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Protéines Smad › Protéines Smad régulées par les récepteurs › Protéine Smad-3 › The transcriptional regulator ZNF398 mediates...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Protéines de la superfamille du TGF bêta › Facteur de croissance transformant bêta › The transcriptional regulator ZNF398 mediates...
questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Conformation moléculaire › Conformation des protéines › Éléments structuraux des protéines › Doigts de zinc › The transcriptional regulator ZNF398 mediates...