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Probing cell identity hierarchies by fate titration and collision during direct reprogramming.

Mol. Syst. Biol. 18:e11129 (2022)
Verlagsversion DOI
Open Access Gold
Creative Commons Lizenzvertrag
Despite the therapeutic promise of direct reprogramming, basic principles concerning fate erasure and the mechanisms to resolve cell identity conflicts remain unclear. To tackle these fundamental questions, we established a single-cell protocol for the simultaneous analysis of multiple cell fate conversion events based on combinatorial and traceable reprogramming factor expression: Collide-seq. Collide-seq revealed the lack of a common mechanism through which fibroblast-specific gene expression loss is initiated. Moreover, we found that the transcriptome of converting cells abruptly changes when a critical level of each reprogramming factor is attained, with higher or lower levels not contributing to major changes. By simultaneously inducing multiple competing reprogramming factors, we also found a deterministic system, in which titration of fates against each other yields dominant or colliding fates. By investigating one collision in detail, we show that reprogramming factors can disturb cell identity programs independent of their ability to bind their target genes. Taken together, Collide-seq has shed light on several fundamental principles of fate conversion that may aid in improving current reprogramming paradigms.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Direct Reprogramming ; Collide-seq ; Fate Conversion ; Reprogramming ; Scrna-seq
ISSN (print) / ISBN 1744-4292
e-ISSN 1744-4292
Quellenangaben Band: 18, Heft: 9, Seiten: , Artikelnummer: e11129 Supplement: ,
Verlag EMBO Press
Begutachtungsstatus Peer reviewed