Cargando…

Repurposing the lineage-determining transcription factor Atoh1 without redistributing its genomic binding sites

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Costa, Aida, Powell, Lynn M., Malaguti, Mattias, Soufi, Abdenour, Lowell, Sally, Jarman, Andrew P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9676683/
https://www.ncbi.nlm.nih.gov/pubmed/36420143
http://dx.doi.org/10.3389/fcell.2022.1016367
_version_ 1784833655756029952
author Costa, Aida
Powell, Lynn M.
Malaguti, Mattias
Soufi, Abdenour
Lowell, Sally
Jarman, Andrew P.
author_facet Costa, Aida
Powell, Lynn M.
Malaguti, Mattias
Soufi, Abdenour
Lowell, Sally
Jarman, Andrew P.
author_sort Costa, Aida
collection PubMed
description 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.
format Online
Article
Text
id pubmed-9676683
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-96766832022-11-22 Repurposing the lineage-determining transcription factor Atoh1 without redistributing its genomic binding sites Costa, Aida Powell, Lynn M. Malaguti, Mattias Soufi, Abdenour Lowell, Sally Jarman, Andrew P. Front Cell Dev Biol Cell and Developmental Biology 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. Frontiers Media S.A. 2022-11-07 /pmc/articles/PMC9676683/ /pubmed/36420143 http://dx.doi.org/10.3389/fcell.2022.1016367 Text en Copyright © 2022 Costa, Powell, Malaguti, Soufi, Lowell and Jarman. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Costa, Aida
Powell, Lynn M.
Malaguti, Mattias
Soufi, Abdenour
Lowell, Sally
Jarman, Andrew P.
Repurposing the lineage-determining transcription factor Atoh1 without redistributing its genomic binding sites
title Repurposing the lineage-determining transcription factor Atoh1 without redistributing its genomic binding sites
title_full Repurposing the lineage-determining transcription factor Atoh1 without redistributing its genomic binding sites
title_fullStr Repurposing the lineage-determining transcription factor Atoh1 without redistributing its genomic binding sites
title_full_unstemmed Repurposing the lineage-determining transcription factor Atoh1 without redistributing its genomic binding sites
title_short Repurposing the lineage-determining transcription factor Atoh1 without redistributing its genomic binding sites
title_sort repurposing the lineage-determining transcription factor atoh1 without redistributing its genomic binding sites
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9676683/
https://www.ncbi.nlm.nih.gov/pubmed/36420143
http://dx.doi.org/10.3389/fcell.2022.1016367
work_keys_str_mv AT costaaida repurposingthelineagedeterminingtranscriptionfactoratoh1withoutredistributingitsgenomicbindingsites
AT powelllynnm repurposingthelineagedeterminingtranscriptionfactoratoh1withoutredistributingitsgenomicbindingsites
AT malagutimattias repurposingthelineagedeterminingtranscriptionfactoratoh1withoutredistributingitsgenomicbindingsites
AT soufiabdenour repurposingthelineagedeterminingtranscriptionfactoratoh1withoutredistributingitsgenomicbindingsites
AT lowellsally repurposingthelineagedeterminingtranscriptionfactoratoh1withoutredistributingitsgenomicbindingsites
AT jarmanandrewp repurposingthelineagedeterminingtranscriptionfactoratoh1withoutredistributingitsgenomicbindingsites