miRNAs: effectors of environmental influences on gene expression and disease

Abstract

Discovered less than a decade ago, micro-RNAs (miRNAs) have emerged as important regulators of gene expression in mammals. They consist of short nucleic acids, on average approximately 22 nucleotides in length. The miRNAs exert their effect by binding directly to target messenger RNAs (mRNAs) and inhibiting mRNA stability and translation. Each miRNA can bind to multiple targets and many miRNAs can bind to the same target mRNA, allowing for a complex pattern of regulation of gene expression. Once bound to their targets, miRNAs can suppress translation of the mRNA by either sequestration or degradation of the message. Thus, miRNAs function as powerful and sensitive posttranscriptional regulators of gene expression. This review will summarize what is known about miRNA biogenesis, expression, regulation, function, mode of action, and role in disease processes with an emphasis on miRNAs in mammals. We discuss some of the methodology employed in miRNA research and the potential of miRNAs as therapeutic targets. The role of miRNAs in signal transduction and cellular stress is reviewed. Lastly, we identify new exciting avenues of research on the role of miRNAs in toxicogenomics and the possibility of epigenetic effects on gene expression.

FIG. 1

Diagram of miRNA processing and function in the cell. Both mRNAs and miRNAs are transcribed by RNA polymerase II in the nucleus. Processing and maturation of miRNAs occurs in a stepwise, compartmentalized manner. In the nucleus Drosha cleaves the long pri-miRNAs. After export to the cytoplasm, a complex with Dicer further processes the miRNAs. The mature miRNA is bound by Ago proteins and GW182 to form a mature particle called miRISC. The miRISC complex interacts with other RNA-binding proteins, such as the ARE-binding protein HuR, that determine cellular location (e.g., accumulation in P-bodies or in polysomes) and translational efficiency. Once in P-bodies, mRNAs can either be stored for later translational activation or be degraded in a stepwise process dependent on cleavage by Ago2 followed by decapping and exonucleolytic decay by XrnI. Cellular stress signals can cause inhibition of translation and accumulation of certain mRNAs in SGs. Both P-bodies and SGs are dynamic structures in the cell and are dependent on the accumulation and turnover of mRNA/miRISC complexes.