Journal
NUCLEIC ACIDS RESEARCH
Volume 49, Issue 4, Pages 1951-1971Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkab032
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Funding
- Academy of Finland
- Cancer Foundation Finland
- Sigrid Juselius Foundation
- UEF Doctoral Programme in Molecular Medicine
- Jalmari and Rauha Ahokas Foundation
- Instrumentarium Foundation
- Finnish Cultural Foundation
- Emil Aaltonen Foundation
- Orion Research Foundation
- Kuopio University Foundation
- Ida Montin Foundation
- Excellence Cluster CellNetworks [EXC81]
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SUMOylation regulates the specificity of GR by modulating its chromatin protein network and accessibility at GR-bound enhancers, affecting chromatin binding and target gene expression.
Glucocorticoid receptor (GR) is an essential transcription factor (TF), controlling metabolism, development and immune responses. SUMOylation regulates chromatin occupancy and target gene expression of GR in a locus-selective manner, but the mechanism of regulation has remained elusive. Here, we identify the protein network around chromatin-bound GR by using selective isolation of chromatin-associated proteins and show that the network is affected by receptor SUMOylation, with several nuclear receptor coregulators and chromatin modifiers preferring interaction with SUMOylation-deficient GR and proteins implicated in transcriptional repression preferring interaction with SUMOylation-competent GR. This difference is reflected in our chromatin binding, chromatin accessibility and gene expression data, showing that the SUMOylation-deficient GR is more potent in binding and opening chromatin at glucocorticoid-regulated enhancers and inducing expression of target loci. Blockage of SUMOylation by a SUMO-activating enzyme inhibitor (ML-792) phenocopied to a large extent the consequences of GR SUMOylation deficiency on chromatin binding and target gene expression. Our results thus show that SUMOylation modulates the specificity of GR by regulating its chromatin protein network and accessibility at GR-bound enhancers. We speculate that many other SUMOylated TFs utilize a similar regulatory mechanism.
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