Glucocorticoid receptor biology through the omics lens: context matters

Abstract

Over the past two decades, advances in omics technologies, combined with classical genetics, have fundamentally reshaped our understanding of glucocorticoid (GC) biology and informed strategies to optimise GC therapy. Traditional models focused on uniform, ligand-dependent gene regulation via the glucocorticoid receptor (GR). In contrast, genome-wide transcriptomic, epigenomic, and proteomic approaches have revealed a far more complex landscape in which GC responses are highly cell-type-specific and context-dependent. High-resolution transcriptomics and single-cell RNA sequencing have uncovered divergent GC-regulated gene networks across immune, metabolic, and structural cell lineages, providing mechanistic insight into both therapeutic efficacy and tissue-specific adverse effects. Epigenomic profiling, including ChIP-seq and ATAC-seq, has shown that chromatin accessibility, enhancer architecture, and GR cistromes vary across cell types and states, thereby shaping transcriptional outcomes. Complementary proteomic studies have defined GR-interacting protein networks that modulate receptor activity. Together, these multi-layered datasets support a systems-level model of GR signalling that integrates chromatin context, transcriptional regulation, and cellular state and begins to explain GC sensitivity, resistance, and context-specific side effects. Emerging multi-omics and single-cell multimodal approaches now enable high-resolution dissection of GC action in complex tissues and disease contexts, advancing precision therapeutic strategies.