Repurposing the lineage-determining transcription factor Atoh1 without redistributing its genomic binding sites.
Atoh1
Gfi1
Pou4f3
cochlea
hair cell
inner ear
pioneer factors
Journal
Frontiers in cell and developmental biology
ISSN: 2296-634X
Titre abrégé: Front Cell Dev Biol
Pays: Switzerland
ID NLM: 101630250
Informations de publication
Date de publication:
2022
2022
Historique:
received:
10
08
2022
accepted:
17
10
2022
entrez:
24
11
2022
pubmed:
25
11
2022
medline:
25
11
2022
Statut:
epublish
Résumé
Although the lineage-determining ability of transcription factors is often modulated according to cellular context, the mechanisms by which such switching occurs are not well known. Using a transcriptional programming model, we found that Atoh1 is repurposed from a neuronal to an inner ear hair cell (HC) determinant by the combined activities of Gfi1 and Pou4f3. In this process, Atoh1 maintains its regulation of neuronal genes but gains ability to regulate HC genes. Pou4f3 enables Atoh1 access to genomic locations controlling the expression of sensory (including HC) genes, but Atoh1 + Pou4f3 are not sufficient for HC differentiation. Gfi1 is key to the Atoh1-induced lineage switch, but surprisingly does not alter Atoh1's binding profile. Gfi1 acts in two divergent ways. It represses the induction by Atoh1 of genes that antagonise HC differentiation, a function in keeping with its well-known repressor role in haematopoiesis. Remarkably, we find that Gfi1 also acts as a co-activator: it binds directly to Atoh1 at existing target genes to enhance its activity. These findings highlight the diversity of mechanisms by which one TF can redirect the activity of another to enable combinatorial control of cell identity.
Identifiants
pubmed: 36420143
doi: 10.3389/fcell.2022.1016367
pii: 1016367
pmc: PMC9676683
doi:
Types de publication
Journal Article
Langues
eng
Pagination
1016367Subventions
Organisme : Medical Research Council
ID : MR/L021099/1
Pays : United Kingdom
Informations de copyright
Copyright © 2022 Costa, Powell, Malaguti, Soufi, Lowell and Jarman.
Déclaration de conflit d'intérêts
Author AC is currently employed by Novartis AG, and previously by AgenTus Therapeutics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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