IRX3 controls a SUMOylation-dependent differentiation switch in adipocyte precursor cells (external link)

Background: IRX3 is associated with obesity risk via the FTO gene locus and is upregulated during early fat cell development in individuals with risk alleles, promoting fat storage. 

Key Findings: 

  1. IRX3 influences adipocyte fate by controlling epigenetic reprogramming. ChIP-seq reveals IRX3 binds to over 300 gene promoters, mainly those involved in SUMOylation and chromatin remodeling.
  2. IRX3 knockout (KO) alters SUMO pathway gene expression, increases SUMOylation, suppresses PPARγ activity and adipogenesis, enhances Wnt signaling, so shifting cell fate toward osteogenesis in 3D cultures. These effects are partially reversible with pharmacological inhibition of SUMOylation. 

Conclusion: IRX3 acts as a master transcriptional regulator, upstream of SUMOylation, to preserve mesenchymal identity and promote adipogenesis while inhibiting osteogenic differentiation.