Glucocorticoid receptor condensates link DNA-dependent receptor dimerization and transcriptional transactivation

F Frank, X Liu, EA Ortlund - Proceedings of the National …, 2021 - National Acad Sciences
Proceedings of the National Academy of Sciences, 2021National Acad Sciences
The glucocorticoid receptor (GR) is a ligand-regulated transcription factor (TF) that controls
the tissue-and gene-specific transactivation and transrepression of thousands of target
genes. Distinct GR DNA-binding sequences with activating or repressive activities have
been identified, but how they modulate transcription in opposite ways is not known. We
show that GR forms phase-separated condensates that specifically concentrate known
coregulators via their intrinsically disordered regions (IDRs) in vitro. A combination of …
The glucocorticoid receptor (GR) is a ligand-regulated transcription factor (TF) that controls the tissue- and gene-specific transactivation and transrepression of thousands of target genes. Distinct GR DNA-binding sequences with activating or repressive activities have been identified, but how they modulate transcription in opposite ways is not known. We show that GR forms phase-separated condensates that specifically concentrate known coregulators via their intrinsically disordered regions (IDRs) in vitro. A combination of dynamic, multivalent (between IDRs) and specific, stable interactions (between LxxLL motifs and the GR ligand-binding domain) control the degree of recruitment. Importantly, GR DNA binding directs the selective partitioning of coregulators within GR condensates such that activating DNAs cause enhanced recruitment of coactivators. Our work shows that condensation controls GR function by modulating coregulator recruitment and provides a mechanism for the up- and down-regulation of GR target genes controlled by distinct DNA recognition elements.
National Acad Sciences