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PubMed2006

MyoD inhibits Fstl1 and Utrn expression by inducing transcription of miR-206.

Terminal differentiation of distinct cell types requires the transcriptional activation of differentiation-specific genes and the suppression of genes associated with the precursor cell. For example, the expression of utrophin (Utrn) is suppressed during skeletal muscle differentiation, and it is replaced at the sarcolemma by the related dystrophin protein. The MyoD transcription factor directly activates the expression of a large number of skeletal muscle genes, but also suppresses the expression of many genes. To characterize a mechanism of MyoD-mediated suppression of gene expression, we investigated two genes that are suppressed in fibroblasts converted to skeletal muscle by MyoD, follistatin-like 1 (Fstl1) and Utrn. MyoD directly activates the expression of a muscle-specific microRNA (miRNA), miR-206, which targets sequences in the Fstl1 and Utrn RNA, and these sequences are sufficient to suppress gene expression in the presence of miR-206. These findings demonstrate that MyoD, in addition to activating muscle-specific genes, induces miRNAs that repress gene expression during skeletal muscle differentiation.

Animals↗

PubMed2024

Suppression of CNS APOE4 Expression by miRNAs Delivered by the S2 AAVrh.10 Capsid-Modified AAV Vector.

The homozygous Apolipoprotein E (APOE4) genotype is the major risk factor for the development of early Alzheimer's disease. Genome engineering studies in mouse models of human APOE4-dependent pathology have established that reduction of APOE4 expression can rescue the phenotype. We hypothesized that APOE4 could be suppressed in the CNS of APOE4 homozygotes using adeno-associated virus (AAV) expression of microRNAs (miRNA) designed to hybridize to APOE mRNA. We screened nine different miRNAs targeting APOE following transfection in HEK293T and Huh7 cells. Optimal APOE suppression was obtained with mir2A (targeting coding region nt330-351) and mirN4 (3' untranslated region nt1142-1162). miRNA expression cassettes were designed with two copies of each of these two miRNAs co-expressed with a mCherry transgene. To optimize delivery of these miRNAs, an engineered AAVrh.10 variant was identified from a screen of multiple peptide insertions into capsid loop IV and substitutions in loop VIII. This led to identifying the AAV.S2 capsid with enhanced transduction of both neurons and glia and enhanced distribution in the brain. The engineered capsid was used to deliver the APOE miRNA suppression cassette to the hippocampus of TRE4 mice (human APOE4 knock-in replacement of the murine apoE locus). Two weeks after intra-hippocampus administration, regional expression of miRNA at the injection site was quantified at the mRNA level relative to an endogenous reference. The AAV.S2 capsid provided 2.31 ± 0.37-fold higher expression of miRNA over that provided by AAVrh.10 (p < 0.05). In the targeted region, a single intra-hippocampus AAV.S2 administration suppressed hippocampal APOE4 mRNA levels by 76.5 ± 3.9% compared with 41.3 ± 3.3% with the same cassette delivered by the wildtype AAVrh.10 capsid (p < 0.0001). We conclude that an expression cassette with two different miRNAs targeting APOE4 delivered by the AAV.S2 capsid will generate highly significant suppression of APOE4 in the CNS.

Dependovirus↗

PubMed2005

Current efforts in the analysis of RNAi and RNAi target genes.

RNAi is RNA interference by short RNAs. It influences gene-expression by down-regulation of mRNAs, typically by complementarity to the 3' UTR (untranslated region) of the mRNA. microRNAs (miRNAs) are short RNAs acting as natural RNAi. miRNAs mediate down-regulation of many mRNAs from developmental genes and transcription factor genes. Natural examples for this additional level of post-transcriptional control are increasing. Suitable computer-based search strategies for new miRNA candidates include precursor folding as well as different compositional search strategies. Example programs for this are presented. New own and other data are provided for an overview on such strategies. A strategy feasible in plants for miRNA target identification is direct base pairing of miRNAs to potential mRNA target 3' UTRs. Correct identification in animals usually requires comparative genomics and conserved UTR regions pairing to conserved miRNA substructures. A number of example programs and target examples for these tasks are examined. Finally, strategies and programs for artificial gene silencing by designed RNAi are explained.

Animals↗

PubMed2026

X-intNMF: a cross- and intra-omics regularized NMF framework for multi-omics integration.

MOTIVATION: The rapid accumulation of multi-omics data presents a valuable opportunity to advance our understanding of complex diseases and biological systems, driving the development of integrative computational methods. However, the complexity of biological processes, spanning multiple molecular layers and involving intricate regulatory interactions, requires models that can capture both intra- and cross-omics relationships. Most existing integration methods primarily focus on sample-level similarities or intra-omics feature interactions, often neglecting the interactions across different omics layers. This limitation can result in the loss of critical biological information and suboptimal performance. To address this gap, we propose X-intNMF, a network-regularized non-negative matrix factorization (NMF) framework that simultaneously integrates intra- and cross-omics feature interactions into a shared low-dimensional representation (see Fig. 1). By modeling these multi-layered relationships, X-intNMF enhances the representation of biological interactions and improves integration quality and prediction accuracy. RESULTS: For evaluation, we applied X-intNMF to predict breast cancer phenotypes and classify clinical outcomes in lung and ovarian cancers using mRNA expression, microRNA expression, and DNA methylation data from TCGA. The results show that X-intNMF consistently outperforms state-of-the-art methods. Ablation studies confirm that incorporating both cross-omics and intra-omics interactions contributes significantly to the model's improved performance. Additionally, survival analysis on 25 TCGA cancer datasets demonstrates that the integrated multi-omics representation offers strong prognostic value for both overall survival and disease-free status. These findings highlight X-intNMF's ability to effectively model multi-layered molecular interactions while maintaining interpretability, robustness, and scalability within the NMF framework. AVAILABILITY AND IMPLEMENTATION: The source code and datasets supporting this study are publicly available at GitHub (https://github.com/compbiolabucf/X-intNMF) and archived on Zenodo (https://doi.org/10.5281/zenodo.18238385).

Multiomics↗

PubMed2026

circASbase: A Comprehensive Database of Alternative Splicing Events in circRNAs.

Although extensive evidence has underscored the critical role of alternative splicing (AS) in generating mature circular RNA (circRNA) isoforms and augmenting their functional diversity, a significant gap remains in the availability of specialized databases housing circRNA AS events. To bridge this gap, we develop circASbase, a pioneering and comprehensive database that catalogs 452,129 AS events in 884,047 full-length circRNAs from 581 samples across 13 species, and provides rich annotations to facilitate understanding the splicing regulation of circRNA. Our findings reveal substantial differences between circRNAs and linear transcripts regarding the distribution and occurrence of AS events, highlighting the unique regulatory landscape of circRNAs. These special splicing events result in functional differences of circRNAs by affecting internal ribosome entry sites, N6-methyladenosine sites, open reading frames, protein features, microRNA targets, and more. In summary, circASbase not only meets the urgent need of the research community for data repositories, but also represents a significant advancement in our understanding of circRNA biology. With its user-friendly interfaces and web-based visualization tools, circASbase is poised to become an indispensable resource for researchers exploring the regulatory mechanisms and functional roles of AS events in circRNAs. This database will continuously drive new insights and discoveries in the field, setting the stage for further advancements in circRNA research. circASbase is freely available at http://reprod.njmu.edu.cn/cgi-bin/circASbase/.

Alternative Splicing↗

PubMed2005

Small regulatory RNAs in mammals.

Mammalian cells harbor numerous small non-protein-coding RNAs, including small nucleolar RNAs (snoRNAs), microRNAs (miRNAs), short interfering RNAs (siRNAs) and small double-stranded RNAs, which regulate gene expression at many levels including chromatin architecture, RNA editing, RNA stability, translation, and quite possibly transcription and splicing. These RNAs are processed by multistep pathways from the introns and exons of longer primary transcripts, including protein-coding transcripts. Most show distinctive temporal- and tissue-specific expression patterns in different tissues, including embryonal stem cells and the brain, and some are imprinted. Small RNAs control a wide range of developmental and physiological pathways in animals, including hematopoietic differentiation, adipocyte differentiation and insulin secretion in mammals, and have been shown to be perturbed in cancer and other diseases. The extent of transcription of non-coding sequences and the abundance of small RNAs suggests the existence of an extensive regulatory network on the basis of RNA signaling which may underpin the development and much of the phenotypic variation in mammals and other complex organisms and which may have different genetic signatures from sequences encoding proteins.

Animals↗

PubMed2006

Non-coding RNA.

The term non-coding RNA (ncRNA) is commonly employed for RNA that does not encode a protein, but this does not mean that such RNAs do not contain information nor have function. Although it has been generally assumed that most genetic information is transacted by proteins, recent evidence suggests that the majority of the genomes of mammals and other complex organisms is in fact transcribed into ncRNAs, many of which are alternatively spliced and/or processed into smaller products. These ncRNAs include microRNAs and snoRNAs (many if not most of which remain to be identified), as well as likely other classes of yet-to-be-discovered small regulatory RNAs, and tens of thousands of longer transcripts (including complex patterns of interlacing and overlapping sense and antisense transcripts), most of whose functions are unknown. These RNAs (including those derived from introns) appear to comprise a hidden layer of internal signals that control various levels of gene expression in physiology and development, including chromatin architecture/epigenetic memory, transcription, RNA splicing, editing, translation and turnover. RNA regulatory networks may determine most of our complex characteristics, play a significant role in disease and constitute an unexplored world of genetic variation both within and between species.

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

Substrate requirements for let-7 function in the developing zebrafish embryo.

MicroRNAs (miRNAs) are involved in the regulation of gene expression at the post-transcriptional level by base pairing to the 3'-UTR (untranslated region) of mRNAs. The let-7 miRNA was first discovered in Caenorhabditis elegans and is evolutionarily conserved. We used zebrafish embryos as a vertebrate in vivo system to study substrate requirements for function of let-7. Injection of a double-stranded let-7 miRNA into the zygotes of zebrafish and frogs causes specific phenotypic defects. Only the antisense strand of the let-7 duplex has biological activity. In addition, co-injected mRNA of gfp fused to the 3'-UTR of a zebrafish lin-41 ortholog (a presumed target of let-7) is silenced by let-7. Point mutant studies revealed that the two let-7 target sites in the lin-41 3'-UTR are both essential and sufficient for silencing. let-7 and mir221 together, but not either of them alone, can silence a construct with one of the let-7 target sites replaced by a target site for mir221, showing that two different miRNAs can provide the required cooperative effect. let-7 target sites can be moved around: they are also functional when positioned in the coding sequence or even in the 5'-UTR of gfp. We took advantage of reporter and phenotypic assays to analyze the activity of all possible point mutant derivatives of let-7 and found that only the 5' region is critical for function of let-7.

3' Untranslated Regions↗

PubMed2005

ASRP: the Arabidopsis Small RNA Project Database.

Eukaryotes produce functionally diverse classes of small RNAs (20-25 nt). These include microRNAs (miRNAs), which act as regulatory factors during growth and development, and short-interfering RNAs (siRNAs), which function in several epigenetic and post-transcriptional silencing systems. The Arabidopsis Small RNA Project (ASRP) seeks to characterize and functionally analyze the major classes of endogenous small RNAs in plants. The ASRP database provides a repository for sequences of small RNAs cloned from various Arabidopsis genotypes and tissues. Version 3.0 of the database contains 1920 unique sequences, with tools to assist in miRNA and siRNA identification and analysis. The comprehensive database is publicly available through a web interface at http://asrp.cgrb.oregonstate.edu.

Arabidopsis↗

PubMed2005

Antisense inhibition of human miRNAs and indications for an involvement of miRNA in cell growth and apoptosis.

Of the over 200 identified mammalian microRNAs (miRNAs), only a few have known biological activity. To gain a better understanding of the role that miRNAs play in specific cellular pathways, we utilized antisense molecules to inhibit miRNA activity. We used miRNA inhibitors targeting miR-23, 21, 15a, 16 and 19a to test efficacy of antisense molecules in reducing miRNA activity on reporter genes bearing miRNA-binding sites. The miRNA inhibitors de-repressed reporter gene activity when a miRNA-binding site was cloned into its 3'-untranslated region. We employed a library of miRNA inhibitors to screen for miRNA involved in cell growth and apoptosis. In HeLa cells, we found that inhibition of miR-95, 124, 125, 133, 134, 144, 150, 152, 187, 190, 191, 192, 193, 204, 211, 218, 220, 296 and 299 caused a decrease in cell growth and that inhibition of miR-21 and miR-24 had a profound increase in cell growth. On the other hand, inhibition of miR-7, 19a, 23, 24, 134, 140, 150, 192 and 193 down-regulated cell growth, and miR-107, 132, 155, 181, 191, 194, 203, 215 and 301 increased cell growth in lung carcinoma cells, A549. We also identified miRNA that when inhibited increased the level of apoptosis (miR-1d, 7, 148, 204, 210, 216 and 296) and one miRNA that decreased apoptosis (miR-214) in HeLa cells. From these screens, we conclude that miRNA-mediated regulation has a complexity of cellular outcomes and that miRNAs can be mediators of regulation of cell growth and apoptosis pathways.

Apoptosis↗

PubMed2005

MicroInspector: a web tool for detection of miRNA binding sites in an RNA sequence.

Regulation of post-transcriptional gene expression by microRNAs (miRNA) has so far been validated for only a few mRNA targets. Based on the large number of miRNA genes and the possibility that one miRNA might influence gene expression of several targets simultaneously, the quantity of ribo-regulated genes is expected to be much higher. Here, we describe the web tool MicroInspector that will analyse a user-defined RNA sequence, which is typically an mRNA or a part of an mRNA, for the occurrence of binding sites for known and registered miRNAs. The program allows variation of temperature, the setting of energy values as well as the selection of different miRNA databases to identify miRNA-binding sites of different strength. MicroInspector could spot the correct sites for miRNA-interaction in known target mRNAs. Using other mRNAs, for which such an interaction has not yet been described, we discovered frequently potential miRNA binding sites of similar quality, which can now be analysed experimentally. The MicroInspector program is easy to use and does not require specific computer skills. The service can be accessed via the MicroInspector web server at http://www.imbb.forth.gr/microinspector.

Base Pairing↗

PubMed2005

miRU: an automated plant miRNA target prediction server.

MicroRNAs (miRNAs) play important roles in gene expression regulation in animals and plants. Since plant miRNAs recognize their target mRNAs by near-perfect base pairing, computational sequence similarity search can be used to identify potential targets. A web-based integrated computing system, miRU, has been developed for plant miRNA target gene prediction in any plant, if a large number of sequences are available. Given a mature miRNA sequence from a plant species, the system thoroughly searches for potential complementary target sites with mismatches tolerable in miRNA-target recognition. True or false positives are estimated based on the number and type of mismatches in the target site, and on the evolutionary conservation of target complementarity in another genome which can be selected according to miRNA conservation. The output for predicted targets, ordered by mismatch scores, includes complementary sequences with mismatches highlighted in colors, original gene sequences and associated functional annotations. The miRU web server is available at http://bioinfo3.noble.org/miRU.htm.

Algorithms↗

PubMed2006

HEN1 recognizes 21-24 nt small RNA duplexes and deposits a methyl group onto the 2' OH of the 3' terminal nucleotide.

microRNAs (miRNAs) and small interfering RNAs (siRNAs) in plants bear a methyl group on the ribose of the 3' terminal nucleotide. We showed previously that the methylation of miRNAs and siRNAs requires the protein HEN1 in vivo and that purified HEN1 protein methylates miRNA/miRNA* duplexes in vitro. In this study, we show that HEN1 methylates both miRNA/miRNA* and siRNA/siRNA* duplexes in vitro with a preference for 21-24 nt RNA duplexes with 2 nt overhangs. We also demonstrate that HEN1 deposits the methyl group on to the 2' OH of the 3' terminal nucleotide. Among various modifications that can occur on the ribose of the terminal nucleotide, such as 2'-deoxy, 3'-deoxy, 2'-O-methyl and 3'-O-methyl, only 2'-O-methyl on a small RNA inhibits the activity of yeast poly(A) polymerase (PAP). These findings indicate that HEN1 specifically methylates miRNAs and siRNAs and implicate the importance of the 2'-O-methyl group in the biology of RNA silencing.

Escherichia coli Proteins↗

PubMed2006

'Evidence of an auxin signal pathway, microRNA167-ARF8-GH3, and its response to exogenous auxin in cultured rice cells'.

MicroRNA167 (miR167) was shown to cleave auxin responsive factor 8 (ARF8) mRNA in cultured rice cells. MiR167 level was found to be controlled by the presence of auxin in the growth medium. When cells grew in auxin-free medium, miR167 level decreased, resulting in an increase in the level of ARF8 mRNA. Cells growing in the normal growth medium containing auxin showed a reversed trend. It was also shown that expression of OsGH3-2, an rice IAA-conjugating enzyme, was positively regulated by ARF8. Delivery of synthesized miR167 into cells led to decrease of both ARF8 mRNA and OsGH3-2 mRNA. This study provides an evidence in which the exogeneous auxin signal is transduced to OsGH3-2 through miR167 and ARF8 in sequence. This proposed auxin signal transduction pathway, auxin-miR167-ARF8-OsGH3-2, could be, in conjunction with the other microRNA-mediated auxin signals, an important one for responding to exogeneous auxin and for determining the cellular free auxin level which guides appropriate auxin responses.

Cells, Cultured↗

PubMed2006

Polycistronic RNA polymerase II expression vectors for RNA interference based on BIC/miR-155.

Vector-based RNA interference (RNAi) has emerged as a valuable tool for analysis of gene function. We have developed new RNA polymerase II expression vectors for RNAi, designated SIBR vectors, based upon the non-coding RNA BIC. BIC contains the miR-155 microRNA (miRNA) precursor, and we find that expression of a short region of the third exon of mouse BIC is sufficient to produce miR-155 in mammalian cells. The SIBR vectors use a modified miR-155 precursor stem-loop and flanking BIC sequences to express synthetic miRNAs complementary to target RNAs. Like RNA polymerase III driven short hairpin RNA vectors, the SIBR vectors efficiently reduce target mRNA and protein expression. The synthetic miRNAs can be expressed from an intron, allowing coexpression of a marker or other protein with the miRNAs. In addition, intronic expression of a synthetic miRNA from a two intron vector enhances RNAi. A SIBR vector can express two different miRNAs from a single transcript for effective inhibition of two different target mRNAs. Furthermore, at least eight tandem copies of a synthetic miRNA can be expressed in a polycistronic transcript to increase the inhibition of a target RNA. The SIBR vectors are flexible tools for a variety of RNAi applications.

Animals↗

PubMed2006

Improved targeting of miRNA with antisense oligonucleotides.

MicroRNAs (miRNAs) are a class of 20-24 nt noncoding RNAs that regulate target mRNAs post-transcriptionally by binding with imperfect complementarity in the 3'-untranslated region (3'-UTR) and inhibiting translation or RNA stability. Current understanding of miRNA biology is limited, and antisense oligonucleotide (ASO) inhibition is a powerful technique for miRNA functionalization in vitro and in vivo, and for therapeutic targeting of miRNAs. Identification of optimal ASO chemistries for targeting miRNAs is therefore of great interest. We evaluated a number of 2'-sugar and backbone ASO modifications for their ability to inhibit miR-21 activity on a luciferase reporter mRNA. ASO modifications that improved target affinity improved miRNA ASO activity, yet the positioning of high-affinity modifications also had dramatically different effects on miRNA activity, suggesting that more than affinity determined the effectiveness of the miRNA ASOs. We present data in which the activity of a modified miRNA ASO was inversely correlated to its tolerability as an siRNA passenger strand, suggesting that a similar mechanism could be involved in the dissociation of miRNA ASOs and siRNA passenger strands. These studies begin to define the factors important for designing improved miRNA ASOs, enabling more effective miRNA functionalization and therapeutic targeting.

Base Pair Mismatch↗

PubMed2006

Comprehensive thermodynamic analysis of 3' double-nucleotide overhangs neighboring Watson-Crick terminal base pairs.

Thermodynamic parameters are reported for duplex formation of 48 self-complementary RNA duplexes containing Watson-Crick terminal base pairs (GC, AU and UA) with all 16 possible 3' double-nucleotide overhangs; mimicking the structures of short interfering RNAs (siRNA) and microRNAs (miRNA). Based on nearest-neighbor analysis, the addition of a second dangling nucleotide to a single 3' dangling nucleotide increases stability of duplex formation up to 0.8 kcal/mol in a sequence dependent manner. Results from this study in conjunction with data from a previous study [A. S. O'Toole, S. Miller and M. J. Serra (2005) RNA, 11, 512.] allows for the development of a refined nearest-neighbor model to predict the influence of 3' double-nucleotide overhangs on the stability of duplex formation. The model improves the prediction of free energy and melting temperature when tested against five oligomers with various core duplex sequences. Phylogenetic analysis of naturally occurring miRNAs was performed to support our results. Selection of the effector miR strand of the mature miRNA duplex appears to be dependent upon the identity of the 3' double-nucleotide overhang. Thermodynamic parameters for 3' single terminal overhangs adjacent to a UA pair are also presented.

Adenine↗