Regulation of microRNA expression and function by nuclear receptor signaling

Abstract

MicroRNAs (miRNAs) are small non-coding RNA transcripts that affect various cellular pathways by serving as regulators of gene expression at the translational and transcriptional level. Nuclear receptors (NRs) are ligand-activated transcription factors that regulate gene transcription by binding to the promoter region or by interacting with other transcription factors. NRs can regulate miRNA expression either at the transcriptional level, or through posttranscriptional maturation by interacting with miRNA processing factors. This review will summarize recent advances in knowledge of the modulation of miRNA expression by NRs. Increased understanding of the molecular basis of miRNA expression may enable new therapeutic interventions that modulate miRNA activities through NR-mediated signaling.

Figure 1

Nuclear receptor regulation of miRNA expression and biogenesis. 1. The miRNA genes are transcribed by RNA polymerase II to produce pri-miRNAs. NRs bind directly to the miRNA gene promoters or interact with other transcription factors that bind to the target miRNA promoters. 2. The pri-miRNAs are cleaved by Drosha and DGCR8 to become pre-miRNAs, which have hairpin-shaped stem-loop structures. ERα inhibits Drosha by direct interaction. 3. The pre-miRNAs are exported to the cytoplasm by Expertin-5 that is induced by estradiol and progestins. 4. The pre-miRNAs undergo further processing by Dicer to become mature miRNAs. The expression of Dicer is increased by estradiol and progestins. 5. The mature miRNAs are loaded to the miRISC to regulate target gene expression. Ago2, a component of the RISC, is induced by estradiol.