Genomics

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Glucocorticoid-induced phosphorylation by CDK9 specifies the coactivator functions of transcriptional cofactor GRIP1 in macrophages


ABSTRACT: Glucocorticoid Receptor (GR) suppresses inflammation by activating anti-inflammatory and repressing pro-inflammatory genes. GR-interacting protein (GRIP)1 of the p160 family has emerged as a unique GR corepressor in macrophages (MΦ), however, whether GRIP1 contributes to GR-activated transcription, and what dictates its context-specific coactivator vs. corepressor properties is unknown. We report that loss of GRIP1 in human and mouse MΦ attenuated GR-mediated induction of several anti-inflammatory targets, revealing a non-redundant function of GRIP1 in coactivation. Moreover, glucocorticoid treatment of quiescent MΦ globally directed GRIP1 toward GR-bound genomic sites dominated by classic palindromic GREs, suggesting its dedicated role as a GR coactivator. Further, GRIP1 N-terminal region was phosphorylated at a serine cluster by Cyclin-Dependent Kinase (CDK)9, which was recruited into GC-induced GR:GRIP1:CDK9 ternary complexes, producing distinct GRIP1 phospho-isoforms at different GREs even associated with the same gene. Functionally, phosphorylation potentiated GRIP1 coactivator properties by facilitating its recruitment and/or creating novel protein:protein interaction surfaces in a GRE-specific manner. Strikingly, GRIP1 function as a GR corepressor was phosphorylation-independent; consistently, no phospho-GRIP1 or CDK9 was detected at GR transrepression sites near pro-inflammatory genes. Thus, liganded GR in MΦ restricts actions of its own coregulator via CDK9-mediated phosphorylation to a subset of complexes driving anti-inflammatory gene transcription.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE99887 | GEO | 2017/09/29

SECONDARY ACCESSION(S): PRJNA389909

REPOSITORIES: GEO

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