An intronic enhancer of Cebpa regulates adipocyte differentiation and adipose tissue development via long-range loop formation.
Journal
Cell proliferation
ISSN: 1365-2184
Titre abrégé: Cell Prolif
Pays: England
ID NLM: 9105195
Informations de publication
Date de publication:
31 Oct 2023
31 Oct 2023
Historique:
revised:
29
08
2023
received:
24
04
2023
accepted:
11
09
2023
medline:
31
10
2023
pubmed:
31
10
2023
entrez:
31
10
2023
Statut:
aheadofprint
Résumé
Cebpa is a master transcription factor gene for adipogenesis. However, the mechanisms of enhancer-promoter chromatin interactions controlling Cebpa transcriptional regulation during adipogenic differentiation remain largely unknown. To reveal how the three-dimensional structure of Cebpa changes during adipogenesis, we generated high-resolution chromatin interactions of Cebpa in 3T3-L1 preadipocytes and 3T3-L1 adipocytes using circularized chromosome conformation capture sequencing (4C-seq). We revealed dramatic changes in chromatin interactions and chromatin status at interaction sites during adipogenic differentiation. Based on this, we identified five active enhancers of Cebpa in 3T3-L1 adipocytes through epigenomic data and luciferase reporter assays. Next, epigenetic repression of Cebpa-L1-AD-En2 or -En3 by the dCas9-KRAB system significantly down-regulated Cebpa expression and inhibited adipocyte differentiation. Furthermore, experimental depletion of cohesin decreased the interaction intensity between Cebpa-L1-AD-En2 and the Cebpa promoter and down-regulated Cebpa expression, indicating that long-range chromatin loop formation was mediated by cohesin. Two transcription factors, RXRA and PPARG, synergistically regulate the activity of Cebpa-L1-AD-En2. To test whether Cebpa-L1-AD-En2 plays a role in adipose tissue development, we injected dCas9-KRAB-En2 lentivirus into the inguinal white adipose tissue (iWAT) of mice to suppress the activity of Cebpa-L1-AD-En2. Repression of Cebpa-L1-AD-En2 significantly decreased Cebpa expression and adipocyte size, altered iWAT transcriptome, and affected iWAT development. We identified functional enhancers regulating Cebpa expression and clarified the crucial roles of Cebpa-L1-AD-En2 and Cebpa promoter interaction in adipocyte differentiation and adipose tissue development.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e13552Subventions
Organisme : The National Key R & D Program of China
ID : 2020YFA0509500
Organisme : The National Key R & D Program of China
ID : 2021YFD1301100
Organisme : National Natural Science Foundation of China
ID : U19A2036
Organisme : National Natural Science Foundation of China
ID : 32225046
Organisme : National Natural Science Foundation of China
ID : 32102512
Organisme : National Natural Science Foundation of China
ID : 32072687
Organisme : The Sichuan Science and Technology Program
ID : 2021ZDZX0008
Organisme : The Sichuan Science and Technology Program
ID : 2022NSFSC0056
Organisme : The Sichuan Science and Technology Program
ID : 2022ZHXC0072
Organisme : The Sichuan Science and Technology Program
ID : 2021YFYZ0009
Organisme : The Major Science and Technology Projects of Tibet Autonomous Region
ID : XZ202101ZD0005N
Informations de copyright
© 2023 The Authors. Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.
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