IRX3 controls a SUMOylation-dependent differentiation switch in adipocyte precursor cells

Nat Commun. 2025 Aug 6;16(1):7248. doi: 10.1038/s41467-025-62361-1.

Jan-Inge Bjune ¹ ² ³, Samantha Laber ⁴, Laurence Lawrence-Archer ¹ ³, Patrizia M C Nothnagel ⁵, Shuntaro Yamada ⁶, Xu Zhao ⁵, Pouda Panahandeh Strømland ³, Niyaz Al-Sharabi ⁶, Kamal Mustafa ⁶, Pål R Njølstad ¹ ⁷, Melina Claussnitzer ¹ ⁸ ⁹ ¹⁰, Roger D Cox ⁴, Pierre Chymkowitch ¹¹, Gunnar Mellgren ^# ¹² ¹³ ¹⁴, Simon N Dankel ^# ¹⁵ ¹⁶ ¹⁷

Affiliations

1 Mohn Research Center for Diabetes Precision Medicine, Department of Clinical Science, University of Bergen, Bergen, Norway.
2 Mohn Nutrition Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway.
3 Hormone Laboratory, Department of Medical Biochemistry and Pharmacology, Haukeland University Hospital, Bergen, Norway.
4 Medical Research Council Harwell Institute, Mammalian Genetics Unit, Harwell Campus, Oxfordshire, UK.
5 Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, Blindern, Oslo, Norway.
6 Center of Translational Oral Research-Tissue engineering, Department of Clinical Dentistry, University of Bergen, Bergen, Norway.
7 Department of Pediatrics and Adolescents, Haukeland University Hospital, Bergen, Norway.
8 The Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
9 Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
10 Department of Medicine, Harvard Medical School, Boston, MA, USA.
11 Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, Blindern, Oslo, Norway. pierre.chymkowitch@ibv.uio.no.
12 Mohn Research Center for Diabetes Precision Medicine, Department of Clinical Science, University of Bergen, Bergen, Norway. gunnar.mellgren@uib.no.
13 Mohn Nutrition Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway. gunnar.mellgren@uib.no.
14 Hormone Laboratory, Department of Medical Biochemistry and Pharmacology, Haukeland University Hospital, Bergen, Norway. gunnar.mellgren@uib.no.
15 Mohn Research Center for Diabetes Precision Medicine, Department of Clinical Science, University of Bergen, Bergen, Norway. simon.dankel@uib.no.
16 Mohn Nutrition Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway. simon.dankel@uib.no.
17 Hormone Laboratory, Department of Medical Biochemistry and Pharmacology, Haukeland University Hospital, Bergen, Norway. simon.dankel@uib.no.
# Contributed equally.

PMID: 40769964 DOI: 10.1038/s41467-025-62361-1

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.

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HY-108702

ML-792

99.76%, SUMO-Activating Enzyme Inhibitor

E1/E2/E3 Enzyme

Cancer

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