Multidirectional interplay between nuclear receptors and microRNAs
Section snippets
Nuclear receptors
Steroid hormone receptors belong to the NRs, one of the largest superfamilies of transcription factors with 48 members in humans. The steroid receptor (SR) subfamily includes the estrogen receptors (ER) α and β, progesterone (PR), androgen (AR), glucocorticoid (GR) and mineralocorticoid (MR) receptors [1]. Upon binding to their cognate hormone, SRs bind to specific DNA elements present in the genome or to other DNA-bound transcription factors, and then regulate the transcription and expression
miRNAs
miRNAs are small non-coding RNAs of 20–25 nucleotides (nt) that have been shown to regulate gene expression in many physiological and developmental pathways in a multitude of different organisms [5]. Generally, miRNAs regulate gene expression by reducing protein levels, either by repressing translation and/or by inducing the degradation of target mRNAs [6]. miRNAs are encoded by specific genes and the miRNA-encoding loci are located in intergenic regions, or in introns or exons of
miRNAs regulate SR levels and signaling
miRNAs contribute to regulating the final output of NR signaling at different levels (Figure 1a). They can directly target the 3′UTR of the NR mRNA itself and/or the 3′UTR of the mRNAs of NR co-regulators or even NR target genes, thereby regulating NR signaling in an indirect manner.
ERα was one of the first NRs whose 3′UTR was shown to be targeted by miRNAs and it is also one of the better-studied examples among NRs. One of the first studies focused on miRNAs that are differentially expressed
ERα is not alone
A study focusing on miRNAs in neurons tested several miRNAs for their ability to repress glucocorticoid signaling and found that miR-18 and miR-124a reduced it in addition to decreasing GR protein levels [29]. Bizarrely, the GR mRNA is not adequately handled by any of the miRNA target prediction programs. They all consider the 3′UTR of the GR mRNA as being only 2.5 kb long, while it is really about 4 kb (see Table 1, and Ref. [29]), and none shows any miRNA target sites beyond 1.5 kb, even though
miRNA also target NR co-regulators
Apart from directly regulating SR expression, several miRNAs are predicted to target NR co-regulators [33], and in several cases, these interactions are experimentally verified [21••, 34, 35, 36•, 37•]. These include AIB1 and SRC-1, which is targeted by a miRNA, miR-206, which was already known to target the ERα mRNA [19••]. Further downstream in the SR signaling pathway, miR-17/20 was found to target cyclin D1, a known ERα target gene. Given the huge number of NR co-regulators and even larger
Regulation of miRNA expression by SRs
The expression and maturation of miRNAs can be regulated at multiple levels. Since they are encoded by genes, mostly transcribed by Pol II, their transcription can naturally be regulated by a variety of transcription factors including SRs (Figure 1b). Some of the early studies focused on profiling expression of miRNAs in various tumors to identify a miRNA-dependent classification (reviewed in Ref. [38]). By now, there are several other investigations that have attempted to profile and to
ERα also regulates miRNA processing and maturation
Apart from regulating the expression of miRNAs at the transcriptional level, ERα appears to be able to regulate the biogenesis of miRNAs: in the nucleus, by regulating the activity of the microprocessor complex in the processing of pri-miRNA to pre-miRNA [45••], and possibly in the cytoplasm, at the step of maturation from pre-miRNA to mature miRNA [21••]. ERα inhibits the maturation of miRNAs by associating with the Drosha complex through the p68/p72 RNA helicases in a ligand-dependent manner,
Conclusions
The interplay between miRNAs and SRs undoubtedly contributes to fine-tuning many physiological and pathological processes. While almost all insights come from studies done on estrogen/steroid signaling, the general themes are likely to hold true for all or most NRs. Future studies will probably uncover additional complexities within ever more intricately linked regulatory networks. For example, it will be interesting to see whether NRs other than the ERα regulate miRNA biogenesis
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We are grateful to Carlos Fitzsimons for having stimulated our thoughts on this review at an early stage and for sharing his own plans. Work in DP's laboratory was supported by the Canton de Genève, the Swiss National Science Foundation, and the Foundation Medic.
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