Number Of miRNA Genes Research Articles

Role of microRNAs in translation regulation and cancer.

MicroRNAs (miRNAs) are pervasively expressed and regulate most biological functions. They function by modulating transcriptional and translational programs and therefore they orchestrate both physiological and pathological processes, such as development, cell differentiation, proliferation, apoptosis and tumor growth. miRNAs work as small guide molecules in RNA silencing, by negatively regulating the expression of several genes both at mRNA and protein level, by degrading their mRNA target and/or by silencing translation. One of the most recent advances in the field is the comprehension of their role in oncogenesis. The number of miRNA genes is increasing and an alteration in the level of miRNAs is involved in the initiation, progression and metastases formation of several tumors. Some tumor types show a distinct miRNA signature that distinguishes them from normal tissues and from other cancer types. Genetic and biochemical evidence supports the essential role of miRNAs in tumor development. Although the abnormal expression of miRNAs in cancer cells is a widely accepted phenomenon, the cause of this dysregulation is still unknown. Here, we discuss the biogenesis of miRNAs, focusing on the mechanisms by which they regulate protein synthesis. In addition we debate on their role in cancer, highlighting their potential to become therapeutic targets.

Methylation in the regulation of the expression of chromosome 3 and microRNA genes in clear-cell renal cell carcinomas

The methylation of CpG islands in promoter regions, together with the interaction of miRNAs with the mRNAs of their target genes on the posttranscriptional level, are complex epigenetic mechanisms that perform the delicate and dynamic regulation of genes and signal transduction pathways in the cell. This review summarizes the results obtained by the authors, as well as the literature data, on the roles of methylation in regulating the protein-coding genes of chromosome 3 and a number of miRNA genes in clear-cell renal cell carcinomas. The results are based on the use of genomic NotI-microarrays (which allow the identification of both methylation and deletions in genes containing CpG islands) and on some other approaches. The application of NotI-microarray technology to the analysis of the chromosome-3 short arm, a region of frequent deletions in tumors, gave us the opportunity to identify many novel genes associated with kidney cancer pathogenesis. The relationship between alterations in the expression leyels and methylation of chromosome 3 genes, kidney cancer progression, and metastasis was shown. New microRNAs involved in kidney cancer pathogenesis were identified as well. The functions of microRNA genes methylated in kidney cancer were discussed.

Upregulation of RHOA and NKIRAS1 genes in lung tumors is associated with loss of their methylation as well as with methylation of regulatory miRNA genes

Methylation of CpG-islands in promoter regions as well as interaction of miRNAs with messenger RNAs of target genes are related to multilayer mechanisms regulating gene expression. The goal of this study was to assess a possibility for miRNA gene methylation to influence indirectly activation of their target genes in lung tumors. By using a unified collection of samples of non-small cell lung cancer, it was demonstrated that elevated levels of mRNA for RHOA and NKIRAS1 genes were significantly (Spearman rank correlation, P < 10(-11)) associated both with loss of methylation in their CpG-islands and methylation in a number of miRNA genes, which, according to the miRWalk database, were predicted to possess regulatory functions. Novel potential regulatory miRNAs for RHOA (miR-9-1/-3, -34b/c, -129-2, -125b-1, -375, -1258) and NKIRAS1 (miR-34b/c, -129-2, -125b-1, -193a, -124a-1/-2/-3, -212, -132) genes in lung cancer were identified.

Expansion of the Human Micro RNA Gene Repertoire in the Human Lineage after the Divergence of Old World and New World Monkeys

It has been widely postulated that micro RNAs (miRNAs) have played an important role in achieving morphological complexity during the course of eumetazoan evolution, because the miRNA repertoire has continually increased along with greater complexity in the genomes of bilaterians and vertebrates. In particular, the miRNA repertoire is dramatically expanded in human. To examine how miRNAs changed during the process of primate evolution, we estimated the evolutionary origins of 1,527 present human miRNAs along the human lineage, after the divergence of eutherian mammals. We constructed an evolutionary profile of the miRNA genes, based on the presence and absence of the known and predicted functional orthologues in six non-human primate species: chimpanzee, gorilla, orangutan, gibbon, macaque, and marmoset and three representative eutherian mammals: bovine, dog and mouse. The functional orthologues were predicted by multiple genome sequence alignments and BLAST searches, followed by four filtering steps. The number of miRNA genes and gene families drastically expanded in the lineage of old world monkey, after the divergence from the common ancestor with new world monkey, at approximately seven-fold higher rates than the earlier stage of primate evolution. The rates of expansion of miRNA and gene families have been slightly declined in hominoids. Comparisons of the number of genes with that of the gene families acquired in each evolutionary period suggested that de novo gene generation, rather than gene duplication, considerably contributed to the generation of new miRNA genes.

Dynamic evolution of mir-17–92 gene cluster and related miRNA gene families in vertebrates

mir-17-92 gene cluster is widely distributed in vertebrates and plays an important role in regulating multiple biological processes. Its dysregulation may be associated with risk of some human cancers. The microRNA (miRNA) members are identified in the three gene families: mir-17, mir-19 and mir-25. Herein we attempted to understand the evolutionary processes and patterns in vertebrates. The three miRNA gene families showed difference in distribution, number of miRNA genes and clustered miRNA genes in the five animal species. Compared to other related gene clusters, mir-17-92 cluster was well-conserved and had more abundant roles in multiple biological processes. These clustered miRNAs showed inconsistent nucleotide divergence patterns across different animal species, even between homologous miRNA genes. Simultaneously, they also indicated inconsistent expression patterns although they were co-transcribed as a polycistronic transcript. Phylogenetic tree based on human pre-miRNA sequences showed that mir-19 gene family was an older miRNA species, while tree based on miRNA gene cluster indicated evolutionary positions of different animal species. The study shows dynamic evolution of the mir-17-92 gene cluster and related miRNA gene families across vertebrates, which may be derived from potential functional implication. miRNA gene cluster should be a better phylogenetic marker than a single miRNA gene to reveal functional and evolutionary relationships.

Origins and Evolution of MicroRNA Genes in Plant Species

MicroRNAs (miRNAs) are among the most important regulatory elements of gene expression in animals and plants. However, their origin and evolutionary dynamics have not been studied systematically. In this paper, we identified putative miRNA genes in 11 plant species using the bioinformatic technique and examined their evolutionary changes. Our homology search indicated that no miRNA gene is currently shared between green algae and land plants. The number of miRNA genes has increased substantially in the land plant lineage, but after the divergence of eudicots and monocots, the number has changed in a lineage-specific manner. We found that miRNA genes have originated mainly by duplication of preexisting miRNA genes or protein-coding genes. Transposable elements also seem to have contributed to the generation of species-specific miRNA genes. The relative importance of these mechanisms in plants is quite different from that in Drosophila species, where the formation of hairpin structures in the genomes seems to be a major source of miRNA genes. This difference in the origin of miRNA genes between plants and Drosophila may be explained by the difference in the binding to target mRNAs between plants and animals. We also found that young miRNA genes are less conserved than old genes in plants as well as in Drosophila species. Yet, nearly half of the gene families in the ancestor of flowering plants have been lost in at least one species examined. This indicates that the repertoires of miRNA genes have changed more dynamically than previously thought during plant evolution.

MicroRNAs: New Players in Cardiac Injury and Protection

MicroRNAs (miRNAs) have emerged as a novel class of endogenous, small, noncoding RNAs that negatively regulate gene expression via degradation or translational inhibition of their target mRNAs. Over 700 miRNAs have been identified and sequenced in humans, and the number of miRNA genes is estimated at more than 1000. Individual miRNA is functionally important as a transcription factor because it has the ability to regulate the expression of multiple genes through binding to its target with imperfect or perfect complement. In the heart, miRNAs have been involved in several clinical scenarios, such as ischemia/reperfusion (I/R) injury and heart failure suggesting that regulation of their function could be used as a novel cardioprotective strategy. In particular, miRNA-1, miRNA-21, miRNA-24, miRNA-29, miRNA-92a, miRNA-126, miRNA-133, miRNA-320, miRNA-199a, miRNA-208, and miRNA-195 have been shown to be regulated after I/R injury. Because tissue miRNAs can be released into circulating blood, they also offer exciting new opportunities for developing sensitive biomarkers, including miRNA-1, miRNA-126, miR-208, and miRNA-499, for acute myocardial infarction and other cardiac diseases.

Evolutionary Conservation of MicroRNA Regulatory Circuits: An Examination of MicroRNA Gene Complexity and Conserved MicroRNA-Target Interactions through Metazoan Phylogeny

During the last decade, a variety of critical biological processes, including early embryo development, cell proliferation, differentiation, apoptosis, and metabolic regularity, have been shown to be genetically regulated by a large gene family encoding a class of tiny RNA molecules termed microRNAs (miRNAs). All miRNAs share a common biosynthetic pathway and reaction mechanisms. The sequence of many miRNAs is found to be conserved, in their mature form, among different organisms. In addition, the evolutionary appearance of multicellular organisms appears to correlate with the appearance of the miRNA pathway for regulating gene expression. The miRNA pathway has the potential to regulate vast networks of gene products in a coordinate manner. Recent evidence has not only implicated the miRNA pathway in regulating a vast array of basic cellular processes but also specialized processes that are required for cellular identity and tissue specificity. A survey of the literature shows that some miRNA pathways are conserved virtually intact throughout phylogeny while miRNA diversity also correlates with speciation. The number of miRNA genes, the expression of miRNAs, and target diversities of miRNAs tend to be positively correlated with morphological complexities observed in animals. Thus, organismal complexity can be estimated by the complexity of the miRNA circuitry. The complexity of the miRNA gene families establishes a link between genotypic complexity and phenotypic complexity in animal evolution. In this paper, we start with the discussion of miRNA conservation. Then we interpret the trends in miRNA conservation to deduce miRNA evolutionary trends in metazoans. Based on these conservation patterns observed in each component of the miRNA regulatory system, we attempt to propose a global insight on the probable consistency between morphological evolution in animals and the molecular evolution of miRNA gene activity in the cell.