Emerging paradigms of regulated microRNA processing

Abstract

MicroRNAs (miRNAs) modulate a broad range of gene expression patterns during development and tissue homeostasis, and in the pathogenesis of disease. The exquisite spatio-temporal control of miRNA abundance is made possible, in part, by regulation of the miRNA biogenesis pathway. In this review, we discuss two emerging paradigms for post-transcriptional control of miRNA expression. One paradigm centers on the Microprocessor, the protein complex essential for maturation of canonical miRNAs. The second paradigm is specific to miRNA families, and requires interaction between RNA-binding proteins and cis-regulatory sequences within miRNA precursor loops.

Figure 1.

Model for regulation of miRNA biogenesis at the Microprocessor. Multiple signaling pathways converge on the Microprocessor via the helicases p68 and p72. These helicases have ATP-dependent and ATP-independent functions. We present a model whereby both functions affect miRNA production. The ATP-independent functions have been linked with recruitment of processing activities to RNA polymerase. This could be used by the miRNA pathway as a manner of recruitment of the Microprocessor to transcription sites. The ATP-dependent role of p68 has been described as maintenance of proper RNA secondary structure to facilitate Drosha cleavage. The components of the RNA polymerase preinitiation complex and Microprocessor are simplified. (TBP) TATA-binding protein; (TAF) TBP-associated factors; (InR) initiator element; (RE) response element.

Figure 2.

Model for regulation of miRNA biogenesis by loop-binding proteins. The processing of let-7 is shown, with contrasting effects of an inhibitor (Lin28) and an activator (KSRP). Both regulators have been linked to the Drosha and Dicer step. In addition, Lin28 promotes degradation of the precursor. Degradation of pri-let-7 has not been demonstrated; however, pri-let-7 does not accumulate in the presence of Lin28 blockade, and therefore may be actively degraded. (TUT4) terminal (U) transferase; (KSRP) KH-type splicing regulatory factor.