Glucocorticoid regulation of the human noncoding genome

Glucocorticoids (GCs) are widely used anti-inflammatory and immunosuppressive agents known to induce substantial changes in gene expression, yet their effects on noncoding RNAs such as long noncoding RNAs (lncRNAs) or microRNAs (miRNAs) remain poorly characterized. Here, we present the first comprehensive and systematic analysis of GC regulation of the noncoding genome across nine human primary cell types from both hematopoietic and nonhematopoietic 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 h posttreatment. We identify more than 2000 GC-responsive noncoding transcripts, including 654 annotated lncRNAs, 1376 novel lncRNAs, and 39 miRNAs. The noncoding RNA response to GCs is highly cell type dependent: 80% of GC-responsive lncRNAs and 97% of miRNAs are unique to a single cell type. Hematopoietic cells exhibit a greater magnitude of lncRNA induction compared with nonhematopoietic cells. Notably, GC treatment uncovers dozens of facultative, stimulus-dependent lncRNAs. GC-responsive transcripts span diverse lncRNA classes, with enrichment of host lncRNAs. In contrast, only a limited number of miRNAs are 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 noncoding transcription contributes to physiological and clinical heterogeneity in GC responses. The newly identified GC-responsive noncoding transcripts could represent biomarkers of GC exposure, determinants of GC sensitivity or resistance, or candidate regulators of tissue-specific GC effects.