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PubMed2004

Expanding roles for miRNAs and siRNAs in cell regulation.

The role of small RNAs as key regulators of mRNA turnover and translation has been well established. Recent advances indicate that the small RNAs termed microRNAs play important roles in cell proliferation, apoptosis and differentiation. Moreover, the microRNA mechanism is an efficient means to regulate production of a diverse range of proteins. As new microRNAs and their mRNA targets rapidly emerge, it is becoming apparent that RNA-based regulation of mRNAs may rival ubiquitination as a mechanism to control protein levels.

Animals↗
PubMed2005

Silence from within: endogenous siRNAs and miRNAs.

Although eukaryotic cells use RNA silencing to defend against transposons and pathogens, they also employ these pathways to regulate the expression of their own genes. Recent results have uncovered new examples of RNA silencing in controlling endogenous gene expression and have revealed novel mechanisms of downregulation. Bioinformatic analyses indicate that target genes in vertebrate species may number in the thousands.

Animals↗
PubMed2007

Repression of protein synthesis by miRNAs: how many mechanisms?

MicroRNAs are approximately 21-nucleotide-long regulators of gene expression that gain access to their target mRNAs by complementary base pairing. Recent studies have revealed that animal microRNAs might take diverse routes to repress gene expression, affecting both target mRNA levels and translation. Mechanistic details of microRNA-mediated repression are starting to emerge but a comprehensive picture of the inhibition, and particularly the effects on mRNA translation, is still lacking. Recent data support different microRNA mechanisms and a role for cytoplasmic processing bodies in the degradation and storage of mRNAs targeted by microRNA regulators.

Animals↗
PubMed2003

miRNAs: micro managers of programmed cell death.

Genomes encode numerous small RNAs, but the function of these molecules has been elusive. Recent studies show that two distinct microRNAs regulate programmed cell death, and provide new mechanisms for the regulation of animal development.

Animals↗
PubMed2026

Disruption of a six-nucleotide miRNA motif improves PKD1 dosage and ameliorates polycystic kidney disease.

Disrupting microRNA interactions to restore protein expression from haploinsufficient genes offers a promising precision-therapy strategy for monogenic disorders. PKD1 heterozygosity underlies autosomal dominant polycystic kidney disease (ADPKD), a disorder affecting nearly 12 million people worldwide, where reduced PKD1 dosage drives progressive cyst formation and kidney failure. We previously identified a 55-bp cis-repressive element in the PKD1 3'UTR. Here, we define a six-nucleotide miR-17 seed match within this element that is sufficient to reproduce PKD1 repression. In vivo base substitution of this motif stabilizes Pkd1 messenger RNA and increases polycystin-1 (PC1) protein levels, producing a robust reduction in cyst growth and preservation of kidney function in mouse models. To therapeutically recapitulate this effect, we developed a steric-blocking oligonucleotide that occludes the motif, stabilizes PKD1 transcript levels, increases PC1 expression, and mitigates cyst-pathogenic events in both murine and patient-derived ADPKD cells. Together, these findings establish a minimal, targetable cis-regulatory motif and provide proof of concept for oligonucleotide-mediated PKD1 derepression, while offering a potentially generalizable strategy to restore other haploinsufficient genes.

Animals↗
PubMed2004

[miRNA: a new regulator of gene expression].

Plant and animal genomes contain an abundance of small genes that produce RNAs of about 22 nucleotides in length, which was dubbed as microRNAs. These newly found endogenous RNAs may participate in a wide range of genetic regulatory pathways and play an important role in the development. This paper is focused on the finding of the microRNAs, its mechanism and function, as well as the methods of research.

Animals↗
PubMed2004

Prediction and identification of Arabidopsis thaliana microRNAs and their mRNA targets.

BACKGROUND: A class of eukaryotic non-coding RNAs termed microRNAs (miRNAs) interact with target mRNAs by sequence complementarity to regulate their expression. The low abundance of some miRNAs and their time- and tissue-specific expression patterns make experimental miRNA identification difficult. We present here a computational method for genome-wide prediction of Arabidopsis thaliana microRNAs and their target mRNAs. This method uses characteristic features of known plant miRNAs as criteria to search for miRNAs conserved between Arabidopsis and Oryza sativa. Extensive sequence complementarity between miRNAs and their target mRNAs is used to predict miRNA-regulated Arabidopsis transcripts. RESULTS: Our prediction covered 63% of known Arabidopsis miRNAs and identified 83 new miRNAs. Evidence for the expression of 25 predicted miRNAs came from northern blots, their presence in the Arabidopsis Small RNA Project database, and massively parallel signature sequencing (MPSS) data. Putative targets functionally conserved between Arabidopsis and O. sativa were identified for most newly identified miRNAs. Independent microarray data showed that the expression levels of some mRNA targets anti-correlated with the accumulation pattern of their corresponding regulatory miRNAs. The cleavage of three target mRNAs by miRNA binding was validated in 5' RACE experiments. CONCLUSIONS: We identified new plant miRNAs conserved between Arabidopsis and O. sativa and report a wide range of transcripts as potential miRNA targets. Because MPSS data are generated from polyadenylated RNA molecules, our results suggest that at least some miRNA precursors are polyadenylated at certain stages. The broad range of putative miRNA targets indicates that miRNAs participate in the regulation of a variety of biological processes.

Arabidopsis↗
PubMed2006

Isolation and identification of gene-specific microRNAs.

Prediction of microRNA (miRNA) candidates using computer programming has identified hundreds and hundreds of genomic hairpin sequences, of which, the functions remain to be determined. Because direct transfection of hairpin-like miRNA precursors (pre)-miRNAs in mammalian cells is not always sufficient to trigger effective RNA-induced gene-silencing complex (RISC) assembly, a key step for RNA interference (RNAi)-related gene silencing, we developed an intronic miRNA-expressing system to overcome this problem, and successfully increased the efficiency and effectiveness of miRNA-associated RNAi induction in vitro and in vivo. By insertion of a hairpin-like pre-miRNA structure into the intron region of a gene, this intronic miRNA biogenesis system has been found to depend on a coupled interaction of nascent precursor messenger RNA transcription and intron excision within a specific nuclear region proximal to genomic perichromatin fibrils. The intronic miRNA was transcribed by RNA type II polymerases, coexpressed with a primary gene transcript, and excised out of its encoding gene transcript by intracellular RNA splicing and processing mechanisms. Currently, some ribonuclease III endonucleases have been found to be involved in the processing of spliced introns and probably facilitating the intronic miRNA maturation. Using this miRNA-expressing system, we have shown for the first time that the intron-derived miRNAs were able to induce strong RNAi effects in not only human and mouse cells but also zebrafish, chicken embryos, and adult mice. Based on the strand complementarity between the designed miRNA and its target gene sequence, we have also developed a miRNA isolation protocol to purify and identify the mature miRNAs generated by the intronic miRNA-expressing system. Several intronic miRNA identities and structures are currently confirmed to be active in vitro and in vivo. According to this proof- of-principle method, we now have the knowledge to design pre-miRNA inserts that are more efficient and effective for the intronic miRNA-expressing system.

Animals↗
PubMed2006

Conservation and divergence of plant microRNA genes.

MicroRNA (miRNA) is one class of newly identified, small, non-coding RNAs that play versatile and important roles in post-transcriptional gene regulation. All miRNAs have similar secondary hairpin structures; many of these are evolutionarily conserved. This suggests a powerful approach to predict the existence of new miRNA orthologs or homologs in other species. We developed a comprehensive strategy to identify new miRNA homologs by mining the repository of available ESTs. A total of 481 miRNAs, belonging to 37 miRNA families in 71 different plant species, were identified from more than 6 million EST sequences in plants. The potential targets of the EST-predicted miRNAs were also elucidated from the EST and protein databases, providing additional evidence for the real existence of these miRNAs in the given plant species. Some plant miRNAs were physically clustered together, suggesting that these miRNAs have similar gene expression patterns and are transcribed together as a polycistron, as observed among animal miRNAs. The uracil nucleotide is dominant in the first position of 5' mature miRNAs. Our results indicate that many miRNA families are evolutionarily conserved across all major lineages of plants, including mosses, gymnosperms, monocots and eudicots. Additionally, the number of miRNAs discovered was directly related to the number of available ESTs and not to evolutionary relatedness to Arabidopsis thaliana, indicating that miRNAs are conserved and little phylogenetic signal exists in the presence or absence of these miRNAs. Regulation of gene expression by miRNAs appears to have existed at the earliest stages of plant evolution and has been tightly constrained (functionally) for more than 425 million years.

Base Sequence↗