Glucocorticoids regulate the human non-coding genome

Glucocorticoids (GCs) are widely used anti-inflammatory and immunosuppressive agents known to induce dramatic changes in gene expression, yet their effects on non-coding RNAs such as long non-coding RNAs (lncRNAs) or microRNAs (miRNAs) remain poorly characterized. We present the first comprehensive and systematic analysis of GC regulation of the non-coding genome across nine human primary cell types from both hematopoietic and non-hematopoietic lineages. In vitro GC treatment was applied to each cell type, with transcriptomic profiling (total RNA-seq and small RNA-seq) at 2 and 6 hours post-treatment. We identified over 2,000 GC-responsive non-coding transcripts, including 654 annotated lncRNAs, 1,376 novel lncRNAs, and 39 miRNAs. The non-coding RNA response to GCs was highly cell type-dependent: 80% of GC-responsive lncRNAs and 97% of miRNAs were unique to a single cell type. Hematopoietic cells exhibited a greater magnitude of lncRNA induction than non-hematopoietic cells. Notably, dozens of facultative lncRNAs (undetectable at baseline) were induced de novo by GC. GC-responsive transcripts spanned diverse lncRNA classes, with enrichment of host lncRNAs. By contrast, only a limited number of miRNAs were GC-responsive. GC regulation of transcript abundance for miRNAs and their host lncRNAs appears to be independent. Our results, which are accessible through an interactive web application, establish a framework for studying how non-coding transcription contributes to physiological and clinical heterogeneity in GC responses. The newly identified GC-responsive non-coding transcripts could represent biomarkers of GC exposure, determinants of GC sensitivity or resistance, or candidate regulators of tissue-specific GC effects.