Role of the chromatin landscape and sequence in determining cell type-specific genomic glucocorticoid receptor binding and gene regulation

Abstract

The genomic loci bound by the glucocorticoid receptor (GR), a hormone-activated transcription factor, show little overlap between cell types. To study the role of chromatin and sequence in specifying where GR binds, we used Bayesian modeling within the universe of accessible chromatin. Taken together, our results uncovered that although GR preferentially binds accessible chromatin, its binding is biased against accessible chromatin located at promoter regions. This bias can only be explained partially by the presence of fewer GR recognition sequences, arguing for the existence of additional mechanisms that interfere with GR binding at promoters. Therefore, we tested the role of H3K9ac, the chromatin feature with the strongest negative association with GR binding, but found that this correlation does not reflect a causative link. Finally, we find a higher percentage of promoter–proximal GR binding for genes regulated by GR across cell types than for cell type-specific target genes. Given that GR almost exclusively binds accessible chromatin, we propose that cell type-specific regulation by GR preferentially occurs via distal enhancers, whose chromatin accessibility is typically cell type-specific, whereas ubiquitous target gene regulation is more likely to result from binding to promoter regions, which are often accessible regardless of cell type examined.

Decoding inflammation, its causes, genomic responses, and emerging countermeasures

“…Hence, the anti‐inflammatory actions of glucocorticoids and NTM are not mutually exclusive and can potentially synergize. In the nucleus, the glucocorticoid receptor binds to the glucocorticoid response elements while also downregulating several proinflammatory genes …”

“…In the nucleus, the glucocorticoid receptor binds to the glucocorticoid response elements while also downregulating several proinflammatory genes. [126][127][128] Besides endogenous cortisol, the other physiologic lipid derivatives, resolvins, control the inflammatory response, accelerating its resolution. Resolvins encompass the three families of lipid mediators limiting innate immune responses and promoting microbial clearance displaying a cytoprotective effect in microbial inflammation.…”

“…In contrast to anti-TNFα monoclonal antibody, anti-inflammatory glucocorticoids downregulate several proinflammatory genes. [126][127][128]146 Still, the anti-inflammatory glucocorticoid function is counteracted by proinflammatory cytokines, TNFα and IL-1β. 147 Moreover, the metabolic side effects of glucocorticosteroids such as hyperglycaemia, hyperlipidemia and osteoporosis are of concern.…”

“…189 The second major intracellular therapy of inflammationmediated diseases is based on the physiologic hormone cortisol that is produced in the adrenal cortex upon stimulation with the adrenocorticotropic hormone (ACTH) secreted by the pituitary gland. [126][127][128]146 Cortisol and its more potent analogs penetrate the cell membrane and bind to the glucocorticoid receptor belonging to the class of nuclear receptors described above. Through binding to distal enhancers whose chromatin accessibility is usually cell-type specific, 128 the glucocorticoid receptor reprogrammes the inflammatory regulome.…”

“…[126][127][128]146 Cortisol and its more potent analogs penetrate the cell membrane and bind to the glucocorticoid receptor belonging to the class of nuclear receptors described above. Through binding to distal enhancers whose chromatin accessibility is usually cell-type specific, 128 the glucocorticoid receptor reprogrammes the inflammatory regulome. After LPS-induced genomic reprogramming, the glucocorticoid receptor produced a similar gene expression to the kind observed before the LPS challenge, while enhancing the expression of metabolic genes.…”