Transcriptional glucocorticoid effects in the brain: Finding the relevant target genes

Glucocorticoids are powerful modulators of brain function. They act via mineralocorticoid and glucocorticoid receptors (MR and GR). These are best understood as transcription factors. Although many glucocorticoid effects depend on the modulation of gene transcription, it is a major challenge to link gene expression to function given the large-scale, apparently pleiotropic genomic responses. The extensive sets of MR and GR target genes are highly specific per cell type, and the brain contains many different (neuronal and non-neuronal) cell types. Next to the set trait of cellular context, the state of other active signaling pathways will affect MR and GR transcriptional activity. Here, we discuss receptor specificity and contextual factors that determine the transcriptional outcome of MR/GR signaling, experimental possibilities offered by single-cell transcriptomics approaches, and reflect on how to make sense of lists of target genes in relation to understanding the functional effects of steroid receptor activation.

Automated summary

Glucocorticoids modulate brain function through the regulation of gene transcription. However, linking gene expression to function is challenging due to the extensive and pleiotropic genomic responses. The transcriptional activity of MR and GR is influenced by cellular context and other active signaling pathways.