Glucocorticoids regulate the human non-coding genome

Abstract

Glucocorticoids (GCs) are the most commonly used anti-inflammatory and immunosuppressive drugs. However, most of the work on this class of drugs has focused on their relationship to the coding genome. It has been demonstrated in recent years that non-coding genes can play important biological roles. Thus, we performed total RNA-seq and small-RNA-seq in 9 primary human cell types: B cells, CD4+ T cells, monocytes, neutrophils, endothelial cells, fibroblasts, myoblasts, osteoblasts, and preadipocytes, treated in vitro with the GC methylprednisolone. We found that the response of lncRNA genes to GCs appears to be strong and cell type-dependent, with hematopoietic cells being more responsive to GCs than non-hematopoietic cells. Among GC-responsive lncRNAs, the intergenic and RNA host subtypes are overrepresented, while antisense lncRNAs are underrepresented. GC regulation of miRNAs appears to be limited to those that are part of a larger transcript. We generated a global map of GC-responsive lncRNAs and microRNAs in the 9 cell types, and an interactive web application to allow exploration of our results. We identified the lncRNA WAKMAR2 as a GC-induced gene that may play a role in GC action in CD4+ T cells and monocytes. WAKMAR2 has been shown to influence the expression of inflammatory cytokines in non-hematopoietic cells. Single-molecule RNA FISH revealed that, in human monocyte-derived macrophages, WAKMAR2 transcripts are primarily cytoplasmic. Ongoing work is aimed at determining whether WAKMAR2 is in fact a GC-induced negative regulator of inflammatory responses in human primary cells.