MicroRNAs: history, biogenesis, and their evolving role in animal development and disease

Abstract

The discovery of microRNAs (miRNAs) in 1993 followed by developments and discoveries in small RNA biology have redefined the biological landscape by significantly altering the longstanding dogmas that defined gene regulation. These small RNAs play a significant role in modulation of an array of physiological and pathological processes ranging from embryonic development to neoplastic progression. Unique miRNA signatures of various inherited, metabolic, infectious, and neoplastic diseases have added a new dimension to the studies that look at their pathogenesis and highlight their potential to be reliable biomarkers. Also, altering miRNA functionality and the development of novel in vivo delivery systems to achieve targeted modulation of specific miRNA function are being actively pursued as novel approaches for therapeutic intervention in many diseases. Here we review the current body of knowledge on the role of miRNAs in development and disease and discuss future implications.

Keywords: animal microRNA; apoptomiR; biomarkers; circulating miRNA; miR; oncomiR.

Figure 1

Canonical microRNA (miRNA) biogenesis pathway: miRNAs are initially transcribed as long, variable-length hairpin RNA substrates called primary miRNAs (pri-miRNAs) directly off the DNA template in the nucleus by RNA polymerase II (A). In the nucleus, these pri-miRNAs are again processed by the Microprocessor, a large complex that includes the RNase type III enzyme called Drosha and the RNA binding protein DGCR8, into ~70- to 120-nucleotide-long premature (pre) hairpin precursor forms called pre-miRNAs (A). The pre-miRNAs are then exported to the cytoplasm by exportin 5 (B), where the loop region of the pre-miRNA is cleaved by the RNAse type III enzyme called Dicer into ~18- to 23-nucleotide-long mature miRNAs (C). A cellular protein called transactivation response RNA binding protein (TRBP) (D) facilitates the entry of the Dicer-miRNA complex into the RNA-induced silencing complex (RISC) that contains Argonaute 2 (Ago2), protein kinase RNA activator (PACT), trinucleotide repeat-containing gene 6A (TNRC6A), and other RNA binding proteins (E). After incorporation of the mature miRNAs into the RNA-induced silencing complex (RISC), the “passenger” strand is degraded, and the “guide” strand is guided to the 3′ UTR of the target messenger RNA (mRNA) to either degrade (in case of perfect base complementarity) or bring about translational inhibition (in case of multiple sequence mismatches between the target mRNA and the miRNA) (F). Mounting evidence suggests that transcripts bound by miRNA-incorporated Ago2 are channeled into structures called P-bodies, resulting in translational repression (G). (Loosely adapted and redrawn from Yeung et al.)