Regulation of MicroRNA Biogenesis: A miRiad of mechanisms

Abstract

microRNAs are small, non-coding RNAs that influence diverse biological functions through the repression of target genes during normal development and pathological responses. Widespread use of microRNA arrays to profile microRNA expression has indicated that the levels of many microRNAs are altered during development and disease. These findings have prompted a great deal of investigation into the mechanism and function of microRNA-mediated repression. However, the mechanisms which govern the regulation of microRNA biogenesis and activity are just beginning to be uncovered. Following transcription, mature microRNA are generated through a series of coordinated processing events mediated by large protein complexes. It is increasingly clear that microRNA biogenesis does not proceed in a 'one-size-fits-all' manner. Rather, individual classes of microRNAs are differentially regulated through the association of regulatory factors with the core microRNA biogenesis machinery. Here, we review the regulation of microRNA biogenesis and activity, with particular focus on mechanisms of post-transcriptional control. Further understanding of the regulation of microRNA biogenesis and activity will undoubtedly provide important insights into normal development as well as pathological conditions such as cardiovascular disease and cancer.

Figure 1

Biogenesis of miRNAs and assembly into RISC complex. RNA pol II generates capped and polyadenylated pri-miRNAs which are processed by Drosha in the nucleus to generate pre-miRNAs. After translocation into the cytoplasm by exportin 5, pre-miRNAs are processed by Dicer to form the mature miRNA/miRNA* duplex. Following processing, miRNAs are assembled into the RISC complex. Only one strand of the duplex is stably associated with the RISC complex. The mature miRNA directs repression of mRNA containing partially complementary miRNA binding sites within the 3'UTR.

Figure 2

miRNA regulatory circuits. A. The cardiac specific miR-208 family is encoded within the introns of myosin heavy chain (MHC) genes. miR-208 targets THARP1, which then down regulates the expression of β-MHC gene. B. Expression of miR-124 is negatively regulated by the binding of the RE1 silencing transcription (REST) factor to the promoter in non-neuronal cells. C. Examples of feed-back regulation of microRNA transcription through the repression of transcription factors.

Figure 3

Intricate network of regulation of let-7 expression and activity by different proteins. Multiple mechanisms give rise to an intricate feed-back loop which controls the expression of let-7 and Lin-28. Lin28, which is highly expressed in undifferentiated, embryonic stem cells, selectively blocks the processing of let-7 miRNAs through multiple mechanisms including Drosha blockade, Dicer blockade, and 3'-uridylation of pre-let-7. The highly regulated expression of let-7 is critical for the control of cellular differentiation and proliferation.

Figure 4

Regulation of miRNA maturation by the TGF-β superfamily signaling. TGF-β and BMP signaling stimulates the production of pre-miR-21 by promoting the Drosha-mediated processing by controlling nuclear localization of R-Smad proteins. Thus, Smads regulate gene expression in two distinct manners; (i) transcriptional regulation by DNA binding and (ii) regulation of miRNA maturation by associating with the Drosha/DGCR8 complex.