Bjune Jan-Inge, Laber Samantha, Lawrence-Archer Laurence, Nothnagel Patrizia M C, Yamada Shuntaro, Zhao Xu, Panahandeh Strømland Pouda, Al-Sharabi Niyaz, Mustafa Kamal, Njølstad Pål R, Claussnitzer Melina, Cox Roger D, Chymkowitch Pierre, Mellgren Gunnar, Dankel Simon N
Mohn Research Center for Diabetes Precision Medicine, Department of Clinical Science, University of Bergen, Bergen, Norway.
Mohn Nutrition Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway.
Nat Commun. 2025 Aug 6;16(1):7248. doi: 10.1038/s41467-025-62361-1.
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.
IRX3 通过 FTO 基因座与肥胖易感性相关联，并且在风险等位基因携带者的早期脂肪生成过程中上调，使脂肪细胞命运转向脂肪储存。然而，这种 IRX3 表达升高如何影响后期发育阶段仍不清楚。在这里，我们表明 IRX3 通过调节表观遗传重编程来调控脂肪细胞命运。在前脂肪细胞中进行的染色质免疫沉淀测序（ChIP-sequencing）鉴定出 300 多个 IRX3 结合位点，主要位于参与 SUMO 化和染色质重塑的基因启动子处。IRX3 基因敲除会改变 SUMO 途径基因的表达，增加整体 SUMO 化，并抑制 PPARγ 活性和脂肪生成。药理学上的 SUMO 化抑制可挽救这些效应。IRX3 基因敲除还会降低 Wnt 相关基因处的 SUMO 占据率，增强 Wnt 信号传导并促进三维培养中的成骨命运。这种命运转换通过 SUMO 化抑制可部分逆转。我们确定 IRX3 是表观遗传程序的关键转录调节因子，在 SUMO 化上游起作用，以维持间充质特性并支持脂肪生成，同时在小鼠胚胎成纤维细胞中抑制成骨作用。
