14-3-3ζ allows for adipogenesis by modulating chromatin accessibility during the early stages of adipocyte differentiation
Objective: We previously established the scaffold protein 14-3-3ζ as a critical regulator of adipogenesis and adiposity, but whether 14-3-3ζ exerted its regulatory functions in mature adipocytes or in adipose progenitor cells (APCs) remained unclear. Methods: To decipher which cell type accounted fo...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-07-01
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| Series: | Molecular Metabolism |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877825000663 |
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| author | Sabri A. Rial Zhipeng You Alexis Vivoli Fédéric Paré Daphné Sean Amal AlKhoury Geneviève Lavoie Mete Civelek Aida Martinez-Sanchez Philippe P. Roux Thomas M. Durcan Gareth E. Lim |
| author_facet | Sabri A. Rial Zhipeng You Alexis Vivoli Fédéric Paré Daphné Sean Amal AlKhoury Geneviève Lavoie Mete Civelek Aida Martinez-Sanchez Philippe P. Roux Thomas M. Durcan Gareth E. Lim |
| author_sort | Sabri A. Rial |
| collection | DOAJ |
| description | Objective: We previously established the scaffold protein 14-3-3ζ as a critical regulator of adipogenesis and adiposity, but whether 14-3-3ζ exerted its regulatory functions in mature adipocytes or in adipose progenitor cells (APCs) remained unclear. Methods: To decipher which cell type accounted for 14-3-3ζ-regulated adiposity, adipocyte- (Adipoq14-3-3ζKO) and APC-specific (Pdgfra14-3-3ζKO) 14-3-3ζ knockout mice were generated. To further understand how 14-3-3ζ regulates adipogenesis, Tandem Affinity Purification (TAP)-tagged 14-3-3ζ-expressing 3T3-L1 preadipocytes (TAP-3T3-L1) were generated with CRISPR-Cas9, and affinity proteomics was used to examine how the nuclear 14-3-3ζ interactome changes during the initial stages of adipogenesis. ATAC-seq was used to determine how 14-3-3ζ depletion modulates chromatin accessibility during differentiation. Results: We show a pivotal role for 14-3-3ζ in APC differentiation, whereby male and female Pdgfra14-3-3ζKO mice displayed impaired or potentiated weight gain, respectively, as well as fat mass. Proteomics revealed that regulators of chromatin remodeling, like DNA methyltransferase 1 (DNMT1) and histone deacetylase 1 (HDAC1), were significantly enriched in the nuclear 14-3-3ζ interactome and their activities were impacted upon 14-3-3ζ depletion. Enhancing DNMT activity with S-Adenosyl methionine rescued the differentiation of 14-3-3ζ-depleted 3T3-L1 cells. ATAC-seq revealed that 14-3-3ζ depletion impacted the accessibility of up to 1,244 chromatin regions corresponding in part to adipogenic genes, promoters, and enhancers during the initial stages of adipogenesis. Finally, 14-3-3ζ-regulated chromatin accessibility correlated with the expression of key adipogenic genes. Conclusion: Our study establishes 14-3-3ζ as a crucial epigenetic regulator of adipogenesis and highlights the usefulness of deciphering the nuclear 14-3-3ζ interactome to identify novel pro-adipogenic factors and pathways. |
| format | Article |
| id | doaj-art-b46ede6cf29b4d929917b2b380cdfd26 |
| institution | DOAJ |
| issn | 2212-8778 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj-art-b46ede6cf29b4d929917b2b380cdfd262025-08-20T03:10:31ZengElsevierMolecular Metabolism2212-87782025-07-019710215910.1016/j.molmet.2025.10215914-3-3ζ allows for adipogenesis by modulating chromatin accessibility during the early stages of adipocyte differentiationSabri A. Rial0Zhipeng You1Alexis Vivoli2Fédéric Paré3Daphné Sean4Amal AlKhoury5Geneviève Lavoie6Mete Civelek7Aida Martinez-Sanchez8Philippe P. Roux9Thomas M. Durcan10Gareth E. Lim11Department of Medicine, Université de Montréal, Montreal, QC, Canada; Cardiometabolic Axis, Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada; Corresponding author. CRCHUM, Tour Viger, Rm 08.734, Rue St. Denis, Montréal, QC, H2X 029, Canada.The Neuro’s Early Drug Discovery Unit (EDDU), McGill University, 3801 University Street, Montreal, QC, H3A 2B4, CanadaDepartment of Medicine, Université de Montréal, Montreal, QC, Canada; Cardiometabolic Axis, Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, CanadaCardiometabolic Axis, Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, CanadaDepartment of Medicine, Université de Montréal, Montreal, QC, Canada; Cardiometabolic Axis, Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, CanadaDepartment of Medicine, Université de Montréal, Montreal, QC, Canada; Cardiometabolic Axis, Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, CanadaInstitute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montréal, QC, Canada; Department of Pathology and Cell Biology, Faculty of Medicine, Université de Montréal, Montréal, QC, CanadaDepartment of Biomedical Engineering, University of Virginia, Charlottesville, United States; Center for Public Health Genomics, University of Virginia, Charlottesville, VA, 22908, United StatesSection of Cell Biology and Functional Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, Hammersmith Hospital, London, UKInstitute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montréal, QC, Canada; Department of Pathology and Cell Biology, Faculty of Medicine, Université de Montréal, Montréal, QC, CanadaThe Neuro’s Early Drug Discovery Unit (EDDU), McGill University, 3801 University Street, Montreal, QC, H3A 2B4, CanadaDepartment of Medicine, Université de Montréal, Montreal, QC, Canada; Cardiometabolic Axis, Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montréal, QC, Canada; Corresponding author. CRCHUM, Tour Viger, Rm 08.482, 900 Rue St. Denis, Montréal, QC, H2X 029, Canada.Objective: We previously established the scaffold protein 14-3-3ζ as a critical regulator of adipogenesis and adiposity, but whether 14-3-3ζ exerted its regulatory functions in mature adipocytes or in adipose progenitor cells (APCs) remained unclear. Methods: To decipher which cell type accounted for 14-3-3ζ-regulated adiposity, adipocyte- (Adipoq14-3-3ζKO) and APC-specific (Pdgfra14-3-3ζKO) 14-3-3ζ knockout mice were generated. To further understand how 14-3-3ζ regulates adipogenesis, Tandem Affinity Purification (TAP)-tagged 14-3-3ζ-expressing 3T3-L1 preadipocytes (TAP-3T3-L1) were generated with CRISPR-Cas9, and affinity proteomics was used to examine how the nuclear 14-3-3ζ interactome changes during the initial stages of adipogenesis. ATAC-seq was used to determine how 14-3-3ζ depletion modulates chromatin accessibility during differentiation. Results: We show a pivotal role for 14-3-3ζ in APC differentiation, whereby male and female Pdgfra14-3-3ζKO mice displayed impaired or potentiated weight gain, respectively, as well as fat mass. Proteomics revealed that regulators of chromatin remodeling, like DNA methyltransferase 1 (DNMT1) and histone deacetylase 1 (HDAC1), were significantly enriched in the nuclear 14-3-3ζ interactome and their activities were impacted upon 14-3-3ζ depletion. Enhancing DNMT activity with S-Adenosyl methionine rescued the differentiation of 14-3-3ζ-depleted 3T3-L1 cells. ATAC-seq revealed that 14-3-3ζ depletion impacted the accessibility of up to 1,244 chromatin regions corresponding in part to adipogenic genes, promoters, and enhancers during the initial stages of adipogenesis. Finally, 14-3-3ζ-regulated chromatin accessibility correlated with the expression of key adipogenic genes. Conclusion: Our study establishes 14-3-3ζ as a crucial epigenetic regulator of adipogenesis and highlights the usefulness of deciphering the nuclear 14-3-3ζ interactome to identify novel pro-adipogenic factors and pathways.http://www.sciencedirect.com/science/article/pii/S221287782500066314-3-3ζAdipogenesisEnergy homeostasisChromatin accessibilityAdipogenic genesEpigenetic regulation |
| spellingShingle | Sabri A. Rial Zhipeng You Alexis Vivoli Fédéric Paré Daphné Sean Amal AlKhoury Geneviève Lavoie Mete Civelek Aida Martinez-Sanchez Philippe P. Roux Thomas M. Durcan Gareth E. Lim 14-3-3ζ allows for adipogenesis by modulating chromatin accessibility during the early stages of adipocyte differentiation Molecular Metabolism 14-3-3ζ Adipogenesis Energy homeostasis Chromatin accessibility Adipogenic genes Epigenetic regulation |
| title | 14-3-3ζ allows for adipogenesis by modulating chromatin accessibility during the early stages of adipocyte differentiation |
| title_full | 14-3-3ζ allows for adipogenesis by modulating chromatin accessibility during the early stages of adipocyte differentiation |
| title_fullStr | 14-3-3ζ allows for adipogenesis by modulating chromatin accessibility during the early stages of adipocyte differentiation |
| title_full_unstemmed | 14-3-3ζ allows for adipogenesis by modulating chromatin accessibility during the early stages of adipocyte differentiation |
| title_short | 14-3-3ζ allows for adipogenesis by modulating chromatin accessibility during the early stages of adipocyte differentiation |
| title_sort | 14 3 3ζ allows for adipogenesis by modulating chromatin accessibility during the early stages of adipocyte differentiation |
| topic | 14-3-3ζ Adipogenesis Energy homeostasis Chromatin accessibility Adipogenic genes Epigenetic regulation |
| url | http://www.sciencedirect.com/science/article/pii/S2212877825000663 |
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