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Determinants of Glucocorticoid Receptor (GR) Transcriptional Specificity and Genomic Occupancy

  • Author(s): So, Alex Steven (Yick-Lun)
  • Advisor(s): Yamamoto, Keith R
  • et al.
Abstract

The glucocorticoid receptor (GR) associates with glucocorticoid response elements (GREs) and regulates selective gene transcription in a cell-specific manner. GREs are typically thought to be composite elements that recruit GR as well as other factors into functional complexes. We assessed whether GR occupancy is commonly a limiting determinant of GRE function as well as the extent to which core GR binding sequences (GBSs) and GRE architecture are conserved at functional loci. We found that GR was bound in A549 cells predominately near genes responsive to glucocorticoids in those cells and not at genes regulated by GR in other cells. The GREs were distributed equally upstream and downstream of the transcription start sites, with 63% of them >10kb from those sites. Strikingly, sequences flanking the GBSs varied among GREs but were conserved at individual GREs. Similarly, although the GBSs across the set of GREs varied extensively around a consensus, the precise sequence at an individual GRE was conserved across species. Thus, we further examined whether sequence conservation of sites resembling GBSs is sufficient to predict GR-occupancy of GREs at genes responsive to glucocorticoids. Indeed, we found that the level of conservation of GBSs at genes up-regulated by glucocorticoids in mouse C3H10T1/2 mesenchymal stem-like cells correlated directly with the extent of occupancy by GR. We conclude that GR occupancy is a primary determinant of glucocorticoid responsiveness and that sequence of GBSs as well as GRE architecture likely harbor gene-specific regulatory information. Moreover, GBS conservation alone is sufficient to predict GR occupancy at induced genes.

In this study, we found that genes important for regulating circadian rhythm were responsive to glucocorticoids in mesenchymal stem cells (MSCs). Thus, we confirmed that GR stimulated rhythmicity in these cells and identified primary GREs at Per1, Per2, and E4bp4 genes. We investigated whether the circadian clock in MSCs became autonomous of GR function after glucocorticoids have initiated it and found that continual GR activity is required for maintaining rhythmicity. Thus, we conclude that GR initiates circadian rhythm through directly activating Per1, Per2, and E4bp4 genes, and that GR function is essential for maintenance of rhythmicity.

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