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Untethering glucocorticoid receptor‐mediated transcriptional repression
Author(s) -
Weikum Emily Rye,
Hudson William,
Ortlund Eric
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1055.13
Subject(s) - psychological repression , glucocorticoid receptor , activator (genetics) , transcription factor , gene , glucocorticoid , dna , regulation of gene expression , biology , microbiology and biotechnology , gene expression , genetics , chemistry , immunology
The glucocorticoid receptor (GR), a ligand regulated transcription factor that controls the expression of thousands of genes driving both up‐ and down‐regulation at equal frequencies. The mechanism of gene activation is quite well understood and involves GR cooperatively dimerizing onto DNA at glucocorticoid response elements (GREs). However, the mechanism of repression is much more debated and is thought to occur though two possible mechanisms, DNA‐dependent and DNA‐independent. The DNA‐dependent mechanism involves direct binding of GR to the newly discovered negative glucocorticoid response elements (nGREs). The DNA‐independent mechanism involves GRs interaction with activator protein‐1 (AP‐1), which is a central transcription factor in immune systems that drives expression of inflammatory response genes. This mechanism, known as “tethering”, is the prevailing model for GR‐mediated repression at inflammatory genes. However, recent discovery of GR‐nGRE interactions lead us to wonder if DNA‐dependent repression was possible at AP‐1 response elements (TREs). We report that GR is able to repress inflammatory genes in the absence of AP‐1, GR binds to TRE sequences in vitro , and crystal structures of GR bound to novel recognition sites located within canonical TRE‐sequences. This data represents a paradigm shift in our understanding of GR‐mediated repression and represents an alternative mechanism to the tethering hypothesis. Support or Funding Information F31 NRSA (1F31GM11397‐01A1)