POU4F3 pioneer activity enables ATOH1 to drive diverse mechanoreceptor differentiation through a feed-forward epigenetic mechanism.
Animals
Basic Helix-Loop-Helix Transcription Factors
/ genetics
Cell Differentiation
Cochlea
/ metabolism
Enhancer Elements, Genetic
Epigenesis, Genetic
Hair Cells, Auditory
/ cytology
Homeodomain Proteins
/ genetics
Humans
Mechanoreceptors
/ metabolism
Merkel Cells
/ metabolism
Mice
Transcription Factor Brn-3C
/ genetics
ATOH1 and POU4F3
Merkel cells
feed-forward epigenetic transcriptional control
inner ear hair cells
mechanoreceptor evolution
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
20 07 2021
20 07 2021
Historique:
entrez:
16
7
2021
pubmed:
17
7
2021
medline:
15
12
2021
Statut:
ppublish
Résumé
During embryonic development, hierarchical cascades of transcription factors interact with lineage-specific chromatin structures to control the sequential steps in the differentiation of specialized cell types. While examples of transcription factor cascades have been well documented, the mechanisms underlying developmental changes in accessibility of cell type-specific enhancers remain poorly understood. Here, we show that the transcriptional "master regulator" ATOH1-which is necessary for the differentiation of two distinct mechanoreceptor cell types, hair cells in the inner ear and Merkel cells of the epidermis-is unable to access much of its target enhancer network in the progenitor populations of either cell type when it first appears, imposing a block to further differentiation. This block is overcome by a feed-forward mechanism in which ATOH1 first stimulates expression of POU4F3, which subsequently acts as a pioneer factor to provide access to closed ATOH1 enhancers, allowing hair cell and Merkel cell differentiation to proceed. Our analysis also indicates the presence of both shared and divergent ATOH1/POU4F3-dependent enhancer networks in hair cells and Merkel cells. These cells share a deep developmental lineage relationship, deriving from their common epidermal origin, and suggesting that this feed-forward mechanism preceded the evolutionary divergence of these very different mechanoreceptive cell types.
Identifiants
pubmed: 34266958
pii: 2105137118
doi: 10.1073/pnas.2105137118
pmc: PMC8307294
pii:
doi:
Substances chimiques
Atoh1 protein, mouse
0
Basic Helix-Loop-Helix Transcription Factors
0
Homeodomain Proteins
0
Pou4f3 protein, mouse
0
Transcription Factor Brn-3C
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NICHD NIH HHS
ID : T32 HD060549
Pays : United States
Organisme : NIDCD NIH HHS
ID : F31 DC018703
Pays : United States
Organisme : NIDCD NIH HHS
ID : F31 DC017376
Pays : United States
Organisme : NIDCD NIH HHS
ID : R01 DC015530
Pays : United States
Organisme : NIDCD NIH HHS
ID : R01 DC015829
Pays : United States
Organisme : NIDCD NIH HHS
ID : T32 DC009975
Pays : United States
Déclaration de conflit d'intérêts
The authors declare no competing interest.
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