Cooperative RNA degradation stabilizes intermediate epithelial-mesenchymal states and supports a phenotypic continuum.
Mathematical biosciences
Molecular mechanism of gene regulation
Journal
iScience
ISSN: 2589-0042
Titre abrégé: iScience
Pays: United States
ID NLM: 101724038
Informations de publication
Date de publication:
21 Oct 2022
21 Oct 2022
Historique:
received:
24
05
2022
revised:
21
08
2022
accepted:
23
09
2022
entrez:
17
10
2022
pubmed:
18
10
2022
medline:
18
10
2022
Statut:
epublish
Résumé
Multiple intermediate epithelial-mesenchymal transition (EMT) states reflecting hybrid epithelial and mesenchymal phenotypes were observed in physiological and pathological conditions. Previous theoretical models explaining multiple EMT states rely on regulatory loops involving transcriptional feedback, which produce three or four attractors. This is incompatible with the observed continuum-like EMT spectrum. Here, we used mass-action-based models to describe post-transcriptional regulations, finding that cooperative RNA degradation via multiple microRNA binding sites can generate four-attractor systems without transcriptional feedback. Furthermore, the newly identified intermediates-enabling circuits are common in the EMT regulatory network, and they can synergize with transcriptional feedback to support phenotypic continuum. Finally, our model predicted a role of miR-101 in multistate EMT, and we identified evidence from single-cell RNA-sequencing data that support the prediction. Our work reveals a previously unknown role of cooperative RNA degradation and microRNAs in EMT, providing a framework that can bridge the gap between mechanistic models and single-cell experiments.
Identifiants
pubmed: 36248730
doi: 10.1016/j.isci.2022.105224
pii: S2589-0042(22)01496-1
pmc: PMC9557027
doi:
Types de publication
Journal Article
Langues
eng
Pagination
105224Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM140462
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA215845
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA217450
Pays : United States
Informations de copyright
© 2022 The Author(s).
Déclaration de conflit d'intérêts
V.Q. is co-founder of Parthenon Therapeutics, Inc., and Duet BioSytems, Inc. The other authors declare no conflict of interest.
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