SUMOylation regulates the protein network and chromatin accessibility at glucocorticoid receptor-binding sites

Glucocorticoid receptor (GR) is an essential transcription factor that regulates metabolism, development, and immune responses. SUMOylation modulates GR’s chromatin occupancy and target gene expression in a locus-selective manner, although the underlying mechanisms have remained elusive.

Using selective isolation of chromatin-associated proteins, we identified the protein network surrounding chromatin-bound GR. Our findings reveal that this network is influenced by receptor SUMOylation. Specifically, several nuclear receptor coregulators and chromatin modifiers preferentially interact with SUMOylation-deficient GR, while proteins involved in transcriptional repression favor interaction with SUMOylation-competent GR.

These differences are reflected in our chromatin binding, chromatin accessibility, and gene expression data. The SUMOylation-deficient GR exhibits greater potency in binding to and opening chromatin at glucocorticoid-regulated enhancers, which results in enhanced expression of target genes. Blockage of SUMOylation using a SUMO-activating enzyme inhibitor (ML-792) largely mimicked the effects of GR SUMOylation deficiency on chromatin binding and gene expression.

In conclusion, our results demonstrate that SUMOylation fine-tunes the specificity of GR by regulating its chromatin protein network and accessibility at GR-bound enhancers. We speculate that many other SUMOylated transcription factors may utilize a similar regulatory mechanism. ML792