Abstract
The glucocorticoid receptor (GR) associates with glucocorticoid response elements (GREs) and regulates selective gene transcription in a cell-specific manner. Native GREs are typically thought to be composite elements that recruit GR as well as other regulatory 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 and GRE architecture are conserved at functional loci. We surveyed 100-kb regions surrounding each of 548 known or potentially glucocorticoid-responsive genes in A549 human lung cells for GR-occupied GREs. 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 positionally conserved at each responsive gene but across the set of responsive genes were distributed equally upstream and downstream of the transcription start sites, with 63% of them >10 kb from those sites. Strikingly, although the core GR binding sequences across the set of GREs varied extensively around a consensus, the precise sequence at an individual GRE was conserved across four mammalian species. Similarly, sequences flanking the core GR binding sites also varied among GREs but were conserved at individual GREs. We conclude that GR occupancy is a primary determinant of glucocorticoid responsiveness in A549 cells and that core GR binding sequences as well as GRE architecture likely harbor gene-specific regulatory information.
Highlights
Introduction reasons on restricted zones just upstream of promoters, where prokaryotic and fungal elements reside
We describe three properties that contribute to this specificity: (1) glucocorticoid receptor (GR) occupancy at genomic glucocorticoid response elements (GREs) appears to be a primary determinant of glucocorticoid responsiveness; (2) the DNA sequences bound by GR vary widely around a consensus, but the precise sequences of individual GREs are highly conserved, suggesting a role for these sequences in gene-specific GR transcriptional regulation; and (3) native chromosomal GREs were generally found to be composite elements, comprised of multiple factor binding sites that were highly variable in composition, but as with the GR binding sequences, highly conserved at individual GREs
To assess the correlation of GR occupancy with glucocorticoid responsiveness, we examined GR binding at three classes of genes in A549 human lung carcinoma cells: first, genes regulated by GR in A549 cells; second, genes regulated by GR in U2OS human osteosarcoma cells but not in A549; third, genes regulated by GR or the androgen receptor (AR) in cells other than A549 or U2OS
Summary
Introduction reasons on restricted zones just upstream of promoters, where prokaryotic and fungal elements reside. More systematic searches for response elements tal, physiological, and environmental states in distinct organs, have revealed dramatic examples, such as an estrogen tissues, and cell types This is achieved by a network of response element 144 kb upstream from the promoter of transcriptional regulatory factors, which receive and inte- the NRIP gene [9], and an intragenic region 65 kb downgrate signaling information and transduce that information stream from the Fkbp promoter that appears to serve as an by binding close to specific target genes to modulate their androgen response element [10]. The glucocorticoid receptor (GR) long-range regulatory mechanisms are likely to facilitate and associates selectively with corticosteroid ligands produced in promote regulatory evolution [11] It has not been the adrenal gland in response to neuroendocrine cues; the determined whether the position of a response element.
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