IRX3 controls a SUMOylation-dependent differentiation switch in adipocyte precursor cells
Abstract IRX3 is linked to predisposition to obesity through the FTO locus and is upregulated during early adipogenesis in risk-allele carriers, shifting adipocyte fate toward fat storage. However, how this elevated IRX3 expression influences later developmental stages remains unclear. Here we show...
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Nature Portfolio
2025-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62361-1 |
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| author | Jan-Inge Bjune Samantha Laber Laurence Lawrence-Archer Patrizia M. C. Nothnagel Shuntaro Yamada Xu Zhao Pouda Panahandeh Strømland Niyaz Al-Sharabi Kamal Mustafa Pål R. Njølstad Melina Claussnitzer Roger D. Cox Pierre Chymkowitch Gunnar Mellgren Simon N. Dankel |
| author_facet | Jan-Inge Bjune Samantha Laber Laurence Lawrence-Archer Patrizia M. C. Nothnagel Shuntaro Yamada Xu Zhao Pouda Panahandeh Strømland Niyaz Al-Sharabi Kamal Mustafa Pål R. Njølstad Melina Claussnitzer Roger D. Cox Pierre Chymkowitch Gunnar Mellgren Simon N. Dankel |
| author_sort | Jan-Inge Bjune |
| collection | DOAJ |
| description | Abstract IRX3 is linked to predisposition to obesity through the FTO locus and is upregulated during early adipogenesis in risk-allele carriers, shifting adipocyte fate toward fat storage. However, how this elevated IRX3 expression influences later developmental stages remains unclear. Here we show that IRX3 regulates adipocyte fate by modulating epigenetic reprogramming. ChIP-sequencing in preadipocytes identifies over 300 IRX3 binding sites, predominantly at promoters of genes involved in SUMOylation and chromatin remodeling. IRX3 knockout alters expression of SUMO pathway genes, increases global SUMOylation, and inhibits PPARγ activity and adipogenesis. Pharmacological SUMOylation inhibition rescues these effects. IRX3 KO also reduces SUMO occupancy at Wnt-related genes, enhancing Wnt signaling and promoting osteogenic fate in 3D cultures. This fate switch is partially reversible by SUMOylation inhibition. We identify IRX3 as a key transcriptional regulator of epigenetic programs, acting upstream of SUMOylation to maintain mesenchymal identity and support adipogenesis while suppressing osteogenesis in mouse embryonic fibroblasts. |
| format | Article |
| id | doaj-art-b3f8242bfc3b489cb6479ce5b591a088 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-b3f8242bfc3b489cb6479ce5b591a0882025-08-20T03:43:16ZengNature PortfolioNature Communications2041-17232025-08-0116112510.1038/s41467-025-62361-1IRX3 controls a SUMOylation-dependent differentiation switch in adipocyte precursor cellsJan-Inge Bjune0Samantha Laber1Laurence Lawrence-Archer2Patrizia M. C. Nothnagel3Shuntaro Yamada4Xu Zhao5Pouda Panahandeh Strømland6Niyaz Al-Sharabi7Kamal Mustafa8Pål R. Njølstad9Melina Claussnitzer10Roger D. Cox11Pierre Chymkowitch12Gunnar Mellgren13Simon N. Dankel14Mohn Research Center for Diabetes Precision Medicine, Department of Clinical Science, University of BergenMedical Research Council Harwell Institute, Mammalian Genetics Unit, Harwell CampusMohn Research Center for Diabetes Precision Medicine, Department of Clinical Science, University of BergenDepartment of Biosciences, Faculty of Mathematics and Natural Sciences, University of OsloCenter of Translational Oral Research-Tissue engineering, Department of Clinical Dentistry, University of BergenDepartment of Biosciences, Faculty of Mathematics and Natural Sciences, University of OsloHormone Laboratory, Department of Medical Biochemistry and Pharmacology, Haukeland University HospitalCenter of Translational Oral Research-Tissue engineering, Department of Clinical Dentistry, University of BergenCenter of Translational Oral Research-Tissue engineering, Department of Clinical Dentistry, University of BergenMohn Research Center for Diabetes Precision Medicine, Department of Clinical Science, University of BergenMohn Research Center for Diabetes Precision Medicine, Department of Clinical Science, University of BergenMedical Research Council Harwell Institute, Mammalian Genetics Unit, Harwell CampusDepartment of Biosciences, Faculty of Mathematics and Natural Sciences, University of OsloMohn Research Center for Diabetes Precision Medicine, Department of Clinical Science, University of BergenMohn Research Center for Diabetes Precision Medicine, Department of Clinical Science, University of BergenAbstract IRX3 is linked to predisposition to obesity through the FTO locus and is upregulated during early adipogenesis in risk-allele carriers, shifting adipocyte fate toward fat storage. However, how this elevated IRX3 expression influences later developmental stages remains unclear. Here we show that IRX3 regulates adipocyte fate by modulating epigenetic reprogramming. ChIP-sequencing in preadipocytes identifies over 300 IRX3 binding sites, predominantly at promoters of genes involved in SUMOylation and chromatin remodeling. IRX3 knockout alters expression of SUMO pathway genes, increases global SUMOylation, and inhibits PPARγ activity and adipogenesis. Pharmacological SUMOylation inhibition rescues these effects. IRX3 KO also reduces SUMO occupancy at Wnt-related genes, enhancing Wnt signaling and promoting osteogenic fate in 3D cultures. This fate switch is partially reversible by SUMOylation inhibition. We identify IRX3 as a key transcriptional regulator of epigenetic programs, acting upstream of SUMOylation to maintain mesenchymal identity and support adipogenesis while suppressing osteogenesis in mouse embryonic fibroblasts.https://doi.org/10.1038/s41467-025-62361-1 |
| spellingShingle | Jan-Inge Bjune Samantha Laber Laurence Lawrence-Archer Patrizia M. C. Nothnagel Shuntaro Yamada Xu Zhao Pouda Panahandeh Strømland Niyaz Al-Sharabi Kamal Mustafa Pål R. Njølstad Melina Claussnitzer Roger D. Cox Pierre Chymkowitch Gunnar Mellgren Simon N. Dankel IRX3 controls a SUMOylation-dependent differentiation switch in adipocyte precursor cells Nature Communications |
| title | IRX3 controls a SUMOylation-dependent differentiation switch in adipocyte precursor cells |
| title_full | IRX3 controls a SUMOylation-dependent differentiation switch in adipocyte precursor cells |
| title_fullStr | IRX3 controls a SUMOylation-dependent differentiation switch in adipocyte precursor cells |
| title_full_unstemmed | IRX3 controls a SUMOylation-dependent differentiation switch in adipocyte precursor cells |
| title_short | IRX3 controls a SUMOylation-dependent differentiation switch in adipocyte precursor cells |
| title_sort | irx3 controls a sumoylation dependent differentiation switch in adipocyte precursor cells |
| url | https://doi.org/10.1038/s41467-025-62361-1 |
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