Publications

MicroRNAs (miRNAs) are an abundant class of small non-protein-coding RNAs that function as negative gene regulators. They regulate diverse biological processes, and bioinformatic data indicates that each miRNA can control hundreds of gene targets, underscoring the potential influence of miRNAs on almost every genetic pathway. Recent evidence has shown that miRNA mutations or mis-expression correlate with various human cancers and indicates that miRNAs can function as tumour suppressors and oncogenes. miRNAs have been shown to repress the expression of important cancer-related genes and might prove useful in the diagnosis and treatment of cancer.

Genes that control cell differentiation and development are frequently mutated in human cancer. Micro (mi)RNAs are small regulatory RNAs that are emerging as important regulators of cell division/differentiation and human cancer genes. In this review, the miRNA cancer connection is discussed and the possibility of using this novel, but potentially powerful new therapy, involving miRNAs, to treat cancers is speculated on. For example, lung cancer is the major cause of cancer deaths in the USA, but existing therapies fail to treat this disease in the overwhelming majority of cases. The let-7 miRNA is one of a number of 'oncomirs', natural miRNA tumor suppressors in lung tissue, which may prove useful in treating lung cancer or enhancing current treatments for lung cancer.

Cytoplasmic processing bodies, or P-bodies, contain a high concentration of enzymes and factors required for mRNA turnover and translational repression. Recent studies provide evidence that the mRNAs silenced by miRNAs are localized to P-bodies for storage or degradation, perhaps in adjacent subcompartments. mRNP remodeling, potentially induced by miRISC or RNA helicase activity, may cause the modification of the translation initiation complex at the 5' end of mRNA, following translational repression and localization to P-bodies. Further remodeling in P-bodies may facilitate access of the decapping complex to the cap structure, thus inducing mRNA degradation. However, with appropriate signals, stored mRNAs in P-bodies could be released and returned to the translational machinery through mechanisms requiring binding of regulatory proteins to the 3' UTR of mRNAs. Here a model is proposed to explain the repression and degradation stages of the mRNAs within PBs. This model includes preservation or disruption of a stable closed loop structure of the mRNAs, compartmentalization in PBs and mRNA escape triggered by additional binding proteins.

Small, inhibitory RNA molecules called microRNAs cause large decreases in target protein levels through a post-transcriptional mechanism. Until recently, it was believed this mechanism operated almost exclusively at a step in translation. However, new work has revealed that microRNAs have a second, post-transcriptional mechanism that accelerates the rate of deadenylation, the initial step of mRNA decay.

A report of the meeting 'Regulatory RNAs', the 71st Cold Spring Harbor Symposium on Quantitative Biology, Cold Spring Harbor, USA, 31 May-5 July 2006.

Cancer is a complex and dynamic disease, involving a variety of changes in gene expression and structure. Traditionally, the study of cancer has focused on protein-coding genes, considering these as the principal effectors and regulators of tumorigenesis. Recent advances, however, have brought non-protein-coding RNA into the spotlight. MicroRNAs (miRNAs), one such class of non-coding RNAs, have been implicated in the regulation of cell growth, differentiation, and apoptosis [1]. While their study is still at an early stage, and their mechanism of action along with their importance in cancer is not yet fully understood, they may provide an important layer of genetic regulation in tumorigenesis, and ultimately become valuable therapeutic tools.

In Caenorhabditis elegans, heterochronic genes constitute a developmental timer that specifies temporal cell fate selection. The heterochronic gene lin-42 is the C. elegans homolog of Drosophila and mammalian period, key regulators of circadian rhythms, which specify changes in behavior and physiology over a 24 hr day/night cycle. We show a role for two other circadian gene homologs, tim-1 and kin-20, in the developmental timer. Along with lin-42, tim-1 and kin-20, the C. elegans homologs of the Drosophila circadian clock genes timeless and doubletime, respectively, are required to maintain late-larval identity and prevent premature expression of adult cell fates. The molecular parallels between circadian and developmental timing pathways suggest the existence of a conserved molecular mechanism that may be used for different types of biological timing.

The let-7 microRNA is phylogenetically conserved and temporally expressed in many animals. C. elegans let-7 controls terminal differentiation in a stem cell-like lineage in the hypodermis, while human let-7 has been implicated in lung cancer. To elucidate let-7's role in temporal control of nematode development, we used sequence analysis and reverse genetics to identify candidate let-7 target genes. We show that the nuclear hormone receptor daf-12 is a let-7 target in seam cells, while the forkhead transcription factor pha-4 is a target in the intestine. Additional likely targets are the zinc finger protein die-1 and the putative chromatin remodeling factor lss-4. Together with the previous identification of the hunchback ortholog hbl-1 as a let-7 target in the ventral nerve cord, our findings show that let-7 acts in at least three tissues to regulate different transcription factors, raising the possibility of let-7 as a master temporal regulator.

During the formation of animal organs, a single regulatory factor can control the majority of cell-fate decisions, but the mechanisms by which this occurs are poorly understood. One such regulator, the nematode transcription factor PHA-4, functions together with various cis-regulatory elements in target genes to regulate spatial and temporal patterning during development of the pharynx.

In C. elegans, heterochronic genes control the timing of cell fate determination during development. Two heterochronic genes, let-7 and lin-4, encode microRNAs (miRNAs) that down-regulate a third heterochronic gene lin-41 by binding to complementary sites in its 3'UTR. let-7 and lin-4 are conserved in mammals. Here we report the cloning and sequencing of mammalian lin-41 orthologs. We find that mouse and human lin-41 genes contain predicted conserved complementary sites for let-7 and the lin-4 ortholog, mir-125, in their 3'UTRs. Mouse lin-41 (Mlin-41) is temporally expressed in developing mouse embryos, most dramatically in the limb buds. Mlin-41 is down-regulated during mid-embryogenesis at the time when mouse let-7c and mir-125 RNA levels are up-regulated. Our results suggest that mammalian lin-41 is temporally regulated by miRNAs in order to direct key developmental events such as limb formation.