Dissecting OCT4 defines the role of nucleosome binding in pluripotency.
Animals
Binding Sites
/ genetics
Chromatin
/ metabolism
Enhancer Elements, Genetic
Female
Fibroblasts
Gene Library
Humans
Mice
Models, Molecular
Mutation
Nucleosomes
/ metabolism
Octamer Transcription Factor-3
/ genetics
Pluripotent Stem Cells
/ physiology
Protein Binding
SOXB1 Transcription Factors
/ metabolism
Journal
Nature cell biology
ISSN: 1476-4679
Titre abrégé: Nat Cell Biol
Pays: England
ID NLM: 100890575
Informations de publication
Date de publication:
08 2021
08 2021
Historique:
received:
01
08
2019
accepted:
01
07
2021
pubmed:
7
8
2021
medline:
21
9
2021
entrez:
6
8
2021
Statut:
ppublish
Résumé
Pioneer transcription factors such as OCT4 can target silent genes embedded in nucleosome-dense regions. How nucleosome interaction enables transcription factors to target chromatin and determine cell identity remains elusive. Here, we systematically dissect OCT4 to show that nucleosome binding is encoded within the DNA-binding domain and yet can be uncoupled from free-DNA binding. Furthermore, accelerating the binding kinetics of OCT4 to DNA enhances nucleosome binding. In cells, uncoupling nucleosome binding diminishes the ability of OCT4 to individually access closed chromatin, while more dynamic nucleosome binding results in expansive genome scanning within closed chromatin. However, both uncoupling and enhancing nucleosome binding are detrimental to inducing pluripotency from differentiated cells. Remarkably, stable interactions between OCT4 and nucleosomes are continuously required for maintaining the accessibility of pluripotency enhancers in stem cells. Our findings reveal how the affinity and residence time of OCT4-nucleosome complexes modulate chromatin accessibility during cell fate changes and maintenance.
Identifiants
pubmed: 34354236
doi: 10.1038/s41556-021-00727-5
pii: 10.1038/s41556-021-00727-5
pmc: PMC7611526
mid: EMS129589
doi:
Substances chimiques
Chromatin
0
Nucleosomes
0
Octamer Transcription Factor-3
0
POU5F1 protein, human
0
SOX2 protein, human
0
SOXB1 Transcription Factors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
834-845Subventions
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/M010996/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/R008795/1
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/M0180404/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/N024028/1
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C65925/A26986
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Nature Limited.
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