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Article: Evaluation of the determinants for improved pluripotency induction and maintenance by engineered SOX17

TitleEvaluation of the determinants for improved pluripotency induction and maintenance by engineered SOX17
Authors
Issue Date23-Aug-2023
PublisherOxford University Press
Citation
Nucleic Acids Research, 2023, v. 51, n. 17, p. 8934-8956 How to Cite?
Abstract

An engineered SOX17 variant with point mutations within its DNA binding domain termed SOX17FNV is a more potent pluripotency inducer than SOX2, yet the underlying mechanism remains unclear. Although wild-type SOX17 was incapable of inducing pluripotency, SOX17FNV outperformed SOX2 in mouse and human pluripotency reprogramming. In embryonic stem cells, SOX17FNV could replace SOX2 to maintain pluripotency despite considerable sequence differences and upregulated genes expressed in cleavage-stage embryos. Mechanistically, SOX17FNV co-bound OCT4 more cooperatively than SOX2 in the context of the canonical SoxOct DNA element. SOX2, SOX17, and SOX17FNV were all able to bind nucleosome core particles in vitro, which is a prerequisite for pioneer transcription factors. Experiments using purified proteins and in cellular contexts showed that SOX17 variants phase-separated more efficiently than SOX2, suggesting an enhanced ability to self-organise. Systematic deletion analyses showed that the N-terminus of SOX17FNV was dispensable for its reprogramming activity. However, the C-terminus encodes essential domains indicating multivalent interactions that drive transactivation and reprogramming. We defined a minimal SOX17FNV (miniSOX) that can support reprogramming with high activity, reducing the payload of reprogramming cassettes. This study uncovers the mechanisms behind SOX17FNV-induced pluripotency and establishes engineered SOX factors as powerful cell engineering tools.


Persistent Identifierhttp://hdl.handle.net/10722/338620
ISSN
2023 Impact Factor: 16.6
2023 SCImago Journal Rankings: 7.048
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorHu, H-
dc.contributor.authorHo, D-
dc.contributor.authorTan, DS-
dc.contributor.authorMacCarthy, C-
dc.contributor.authorYu, C-
dc.contributor.authorWeng, M-
dc.contributor.authorSchöler, H-
dc.contributor.authorJauch, R-
dc.date.accessioned2024-03-11T10:30:15Z-
dc.date.available2024-03-11T10:30:15Z-
dc.date.issued2023-08-23-
dc.identifier.citationNucleic Acids Research, 2023, v. 51, n. 17, p. 8934-8956-
dc.identifier.issn0305-1048-
dc.identifier.urihttp://hdl.handle.net/10722/338620-
dc.description.abstract<p>An engineered SOX17 variant with point mutations within its DNA binding domain termed SOX17FNV is a more potent pluripotency inducer than SOX2, yet the underlying mechanism remains unclear. Although wild-type SOX17 was incapable of inducing pluripotency, SOX17FNV outperformed SOX2 in mouse and human pluripotency reprogramming. In embryonic stem cells, SOX17FNV could replace SOX2 to maintain pluripotency despite considerable sequence differences and upregulated genes expressed in cleavage-stage embryos. Mechanistically, SOX17FNV co-bound OCT4 more cooperatively than SOX2 in the context of the canonical SoxOct DNA element. SOX2, SOX17, and SOX17FNV were all able to bind nucleosome core particles <em>in vitro</em>, which is a prerequisite for pioneer transcription factors. Experiments using purified proteins and in cellular contexts showed that SOX17 variants phase-separated more efficiently than SOX2, suggesting an enhanced ability to self-organise. Systematic deletion analyses showed that the N-terminus of SOX17FNV was dispensable for its reprogramming activity. However, the C-terminus encodes essential domains indicating multivalent interactions that drive transactivation and reprogramming. We defined a minimal SOX17FNV (miniSOX) that can support reprogramming with high activity, reducing the payload of reprogramming cassettes. This study uncovers the mechanisms behind SOX17FNV-induced pluripotency and establishes engineered SOX factors as powerful cell engineering tools.</p>-
dc.languageeng-
dc.publisherOxford University Press-
dc.relation.ispartofNucleic Acids Research-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.titleEvaluation of the determinants for improved pluripotency induction and maintenance by engineered SOX17-
dc.typeArticle-
dc.identifier.doi10.1093/nar/gkad597-
dc.identifier.scopuseid_2-s2.0-85172424818-
dc.identifier.volume51-
dc.identifier.issue17-
dc.identifier.spage8934-
dc.identifier.epage8956-
dc.identifier.eissn1362-4962-
dc.identifier.isiWOS:001052274200001-
dc.identifier.issnl0305-1048-

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