Multidirectional interplay between nuclear receptors and microRNAs

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Nuclear receptors (NRs) form one of the largest superfamilies of transcription factors in metazoans. MicroRNAs (miRNAs) are small non-coding RNAs that bind the 3′ untranslated region (3′UTR) of target mRNAs to reduce their stability and/or translation. miRNAs can directly regulate the protein output of target NR mRNAs, and, conversely, the expression of miRNAs can be modulated by NRs at the transcriptional level. At least one NR also regulates the posttranscriptional maturation of miRNAs by interacting with miRNA processing factors via NR co-regulators. Moreover, miRNAs regulate NR signaling by targeting the mRNAs of NR co-regulators and target genes. This complex set of interactions also leads to an extensive network of feedback and feedforward regulatory loops.

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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