Integrating the MicroRNome into the study of lung disease

Abstract

Over the last 15 years, investigators have identified small noncoding RNAs as regulators of gene expression. One type of noncoding RNAs are termed microRNAs (miRNAs). miRNAs are evolutionary conserved, approximately 22-nucleotide single-stranded RNAs that target genes by inducing mRNA degradation or by inhibiting translation. miRNAs are implicated in many critical cellular processes, including apoptosis, proliferation, and differentiation. Furthermore, it is estimated that miRNAs may be responsible for regulating the expression of nearly one-third of the human genome. Despite the identification of greater than 500 mature miRNAs, very little is known about their biological functions and functional targets. In the last 5 years, researchers have increasingly focused on the functional relevance and role that miRNAs play in the pathogenesis of human disease. miRNAs are known to be important in solid organ and hematological malignancies, heart disease, as potential modulators of the immune response, and organ development. It is anticipated that miRNA analysis will emerge as an important complement to proteomic and genomic studies to further our understanding of disease pathogenesis. Despite the application of genomics and proteomics to the study of human lung disease, few studies have examined miRNA expression. This perspective is not meant to be an exhaustive review of miRNA biology but will provide an overview of both miRNA biogenesis and our current understanding of the role of miRNAs in lung disease as well as a perspective on the importance of integrating this analysis as a tool for identifying and understanding the biological pathways in lung-disease pathogenesis.

Figure 1.

miRNA processing. miRNAs are first transcribed as long primary transcripts by RNA polymerase II into primary miRNAs (pri-miRNAs). While in the nucleus, an RNase termed “Drosha” cleaves both strands of the pri-miRNA to release a 70- to 100-nucleotide stem loop termed “precursor miRNA” (pre-miRNA). The pre-miRNA is exported from the nucleus to the cytoplasm by Exportin5/RanGTP. Once in the cytoplasm, a second RNase III, termed “Dicer,” in conjunction with a double-stranded RNA binding domain cleaves the pre-miRNA, releasing an approximately 22-nucleotide RNA. A single strand of the duplex is released and incorporated into the miRNA-induced silencing complex (miRISC) while the other strand is degraded. MiRISCs guide miRNAs to the target mRNA to affect either mRNA degradation or translational inhibition. This is partially accomplished through core base-pair complementarity between the miRNA 5′region (termed the “seed sequence”) and target mRNA 3′ UTR. miRNA may also bind to the 5′ UTR and suppress or enhance translation following binding to AU-rich elements.

Figure 2.

miRNA regulation. MiRNA regulation is multifactorial including (A) impaired processing (B) methylation (C) target 3′UTR polymorphism (D) homozygous deletion, (E) amplification, (F) translocation, (G) miRNA/miRNA targeting and (H) environmental factors.