MicroRNA: a new entrance to the broad paradigm of systems molecular medicine

Abstract

Systems molecular medicine is the science of combining systems biology with molecular analysis and intervention to address clinically relevant questions. MicroRNAs (miRNAs) appear particularly suitable to serve as hubs of regulatory networks underlying complex diseases. Clear experimental evidence for coordinated regulation of a large number of genes by miRNAs, however, is still rare. It leaves open several fundamental questions that are important for determining the value of miRNA in complex regulatory networks and in systems molecular medicine. Physiological genomics is a powerful approach for addressing these open questions.

MicroRNAs (miRNAs) are endogenous small RNA molecules that regulate gene expression. A mammalian genome encodes several hundred miRNAs. Typically, a strand of a mature miRNA can bind to the 3′-untranslated region (UTR) of a target mRNA through imperfect base pairing and reduce the expression level of the target protein through translational repression or decreases in mRNA stability. Several recent articles have reviewed the current understanding of miRNA biogenesis and function (4, 5, 6, 16), as well as the relevance of miRNA to specific areas of physiology and disease (15).

A particularly exciting possibility is that miRNA could be one of the cornerstones for a new, broad paradigm of systems molecular medicine (13). Systems molecular medicine is the science of combining systems biology with molecular analysis and intervention to address clinically relevant questions (Fig. 1). A central task of systems molecular medicine is to understand and assemble molecular and functional regulatory networks that underlie complex physiological processes and diseases. It is widely accepted that complex physiological processes and diseases are unlikely to be determined by one gene or one pathway. Instead, networks of regulatory mechanisms are likely involved. miRNAs could play a crucial role in these regulatory networks.

Fig. 1.

Systems molecular medicine combines systems biology and molecular analysis and intervention to address questions that are clinically relevant.

Each animal miRNA has been predicted to target dozens to hundreds of genes because the binding of miRNA to 3′-UTR does not require perfect complementarities. The promiscuity makes it possible for a miRNA to regulate several genes in a pathway or even multiple pathways. The effects could simply be parallel but could also be coordinated (additive, synergistic, or antagonistic). Any coordinated actions on multiple target genes would provide a powerful mechanism for a single miRNA to have significant impacts on a complex regulatory network and ultimately the physiological process or disease (Fig. 2). Evidence for coordinated effects of an miRNA is beginning to emerge. For example, miR-29 has been shown to simultaneously regulate several extracellular matrix genes, possibly contributing to tumor metastasis and cardiac fibrosis (17, 20).

Fig. 2.

MicroRNA (miRNA) as a hub of regulatory networks underlying complex disease. A single miRNA could simultaneously contribute to the regulation of several components of a pathway, multiple pathways in a regulatory network, or even a cluster of diseases. The hypothetical regulatory network shown here is an abstraction of the one reported in Ref. 14, which was derived from Bayesian dependency analysis and functional annotation of gene expression profiles in Dahl salt-sensitive rats. 1-1, gene #1 in pathway #1; 1-6-a, a gene that is co-regulated with gene 1-6 but has not been shown to be part of pathway #1.

Experimental evidence for coordinated regulation of a large number of genes by miRNAs, however, is still rare. It leaves open several fundamental questions that are important for determining the value of miRNA in complex regulatory networks and in systems molecular medicine. If an miRNA often regulates multiple genes that do not have close functional relationships, how does an miRNA achieve any specificity for its effect on cellular and organ systems function? It is possible that target genes of an miRNA may have functional connections among them that are not yet recognized. It is also possible that the specificity of the effect of an miRNA may be partially determined by which target mRNAs are present in a given biological setting, which would suggest interaction between the miRNA mechanism and other mechanisms that regulate gene expression. Consistent with the notion of miRNAs working with other mechanisms to fine-tune gene expression, many studies have shown that the effect of an miRNA on the abundance of a target is often modest. That also leads to the question of the regulatory relationship between different miRNAs and between miRNAs and their host or adjacent protein-encoding genes. Another fundamental question is the role of the second strand of a mature miRNA. One strand of the mature miRNA often dominates, but both strands are present at substantial levels in some cases (11). It is largely unclear what the implications would be to express two strands of an miRNA, each targeting a different set of genes. In addition, multiple miRNAs might work together to regulate a single target.

The complexity of the action of miRNAs calls for comprehensive, integrative approaches to examining the effect of miRNAs. Notably, advanced proteomic techniques have begun to be utilized in the analysis of widespread effects of miRNAs (8, 18). Other approaches that have been used include large-scale sequencing of miRNA (11) and potential miRNA targets, mRNA expression profiling, and bioinformatic modeling. Sequencing of cleaved fragments of mRNAs has been used to identify miRNA targets (1, 7), the applicability of which would depend on the extent to which miRNAs induce mRNA cleavage in a given species.

The potential power of miRNAs as key regulators of complex regulatory networks and the necessary application of genome- or subgenome-scale analyses make miRNA research an appealing topic for publication in Physiological Genomics. Ikeda et al. (10) examined miRNA expression profiles in 67 human left ventricular samples from control subjects or patients with ischemic cardiomyopathy, dilated cardiomyopathy, or aortic stenosis. They found distinct as well as common miRNA expression patterns associated with different types of heart disease. The study added to an exploding area of research on miRNA in the cardiovascular system as commented by van Rooij and Olson (19) and reviewed by Zhang (21) and Latronico et al. (12). Zhang (21) further proposed the concept of microRNomics as a new approach to studying and understanding disease biology. Bhaskaran and colleagues (2) analyzed miRNA expression profiles and found miR-127 to be highly expressed at the late stage of rat fetal lung development. Early overexpression of miR-127 in fetal lung organ culture resulted in signs of improper development. Coutinho et al. (3) used a sequencing approach to discover bovine miRNAs and assess their abundance in bovine embryo, thymus, small intestine, and lymph node. A meta-analysis of mRNA expression profiles suggested an enrichment of predicted miRNA targets in genes with a predominantly strong negative connectivity (9).

These studies demonstrated the power of genomic and genome-related approaches in the study of miRNA. Further integration of genome-related approaches with physiological and clinical approaches will be valuable for further elucidating the role of miRNAs in systems molecular medicine.

GRANTS

The author is supported by National Heart, Lung, and Blood Institute Grants HL-077263, HL-082798, and HL-029587.