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PubMed2005

Polymorphisms in human pre-miRNAs.

MicroRNAs constitute a growing class of non-coding RNAs that are thought to regulate gene expression via translational repression. MicroRNAs are initially transcribed as several hundred-nucleotide pri-miRNAs and are then processed to approximately 60-nucleotide hairpin pre-miRNAs. We hypothesized that polymorphisms in both pre-miRNA and mature microRNA modify various biological processes by influencing the processing and/or target selection of microRNAs. In the present study, we sequenced 173 human pre-miRNA genome regions in 96 subjects and found 10 polymorphisms in the 10 pre-miRNA hairpin regions. Although most of these polymorphisms seem to have no effect on microRNA processing, we identified a C to A polymorphism in the mature miR-30c-2 sequence. This polymorphism may alter target selection and thus exert profound biological effects. To the best of our knowledge, this is the first report of polymorphisms in pre-miRNAs.

Base Sequence↗

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↗

PubMed2005

BIC and miR-155 are highly expressed in Hodgkin, primary mediastinal and diffuse large B cell lymphomas.

In a previous study we demonstrated high expression of the non-coding BIC gene in the vast majority of Hodgkin's lymphomas (HLs). Evidence suggesting that BIC is a primary microRNA transcript containing the mature microRNA-155 (miR-155) as part of a RNA hairpin is now accumulating. We therefore analysed HL cell lines and tissue samples to determine whether miR-155 is also expressed in HL. High levels of miR-155 could be demonstrated, indicating that BIC is processed into a microRNA in HL. Most non-HL subtypes were negative for BIC as determined by RNA-ISH. However, in diffuse large B cell lymphoma (DLBCL) and primary mediastinal B cell lymphoma (PMBL), significant percentages of positive tumour cells were observed in 12/18 and 8/8 cases. A higher proportion of tumour cells were positive for BIC in DLBCL with activated B cell-like phenotype than in DLBCL with germinal centre B cell-like phenotype. Differential BIC expression was confirmed by qRT-PCR analysis. Northern blot analysis showed expression of miR-155 in all DLBCL and PMBL derived cell lines and tissue samples analysed. In summary, we demonstrate expression of primary microRNA BIC and its derivative miR-155 in HL, PMBL and DLBCL.

Cell Line, Tumor↗

PubMed2004

miRNAs on the move: miRNA biogenesis and the RNAi machinery.

Recent advances have led to a more detailed understanding of RNA interference and its role in microRNA biogenesis and function. Primary microRNA transcripts are processed by the RNaseIII nuclease, Drosha, and are exported from the nucleus by Exportin-5. Dicer cleaves microRNAs into their mature forms, which can be incorporated into effector complexes that mediate gene silencing activities. The 3' two-nucleotide overhang structure, a signature of RNaseIII cleavage, has been identified as a critical specificity determinant in targeting and maintaining small RNAs in the RNA interference pathway. MicroRNA functional analyses and genetic and biochemical interrogation of components of the pathway are starting to provide a glimpse at the range of biological processes and phenomena regulated by RNA interference.

Animals↗

PubMed2026

Aldosterone suppresses Na+/H+ exchanger-3 expression through miR-204-5P-mediated posttranscriptional regulation in distal colon.

Na+/H+ exchanger-3 (NHE3) is a major mediator of electroneutral NaCl absorption in the intestine and colon. In the distal colon, chronic aldosterone exposure suppresses NHE3 expression, but the molecular mechanism responsible for this regulation remains unclear. Here, we tested whether aldosterone represses NHE3 through microRNA-dependent posttranscriptional regulation. Transcriptomic analysis of distal colon from dietary Na+-depleted rats identified miR-204-5P (miR-204-5P) as markedly upregulated. Aldosterone increased miR-204-5P abundance and concomitantly reduced NHE3 mRNA, protein expression, and transport activity in rat and human distal colonic epithelium and in SK-CO15 cells. Bioinformatic and reporter analyses identified a conserved miR-204-5P binding site within the NHE3 3'-untranslated region, and miR-204-5P mimic transfection markedly suppressed NHE3 expression and transport activity without affecting other Na+/H+ exchanger isoforms. These findings identify a previously unrecognized aldosterone-microRNA signaling pathway that mediates chronic repression of NHE3 and provide new insight into hormonal regulation of colonic Na+ absorption.NEW & NOTEWORTHY This study identifies a previously unrecognized aldosterone-microRNA signaling mechanism regulating colonic Na+ absorption. We demonstrate that aldosterone induces miR-204-5P, which directly targets the NHE3 3'-untranslated region and suppresses NHE3 expression and transport activity in distal colonic epithelium. These findings reveal a microRNA-mediated pathway linking mineralocorticoid signaling to long-term inhibition of electroneutral NaCl absorption, providing new insight into hormonal regulation of intestinal electrolyte transport.

Animals↗

PubMed2006

Tcl1 expression in chronic lymphocytic leukemia is regulated by miR-29 and miR-181.

B-cell chronic lymphocytic leukemia (B-CLL) is the most common human leukemia in the world. Deregulation of the TCL1 oncogene is a causal event in the pathogenesis of the aggressive form of this disease as was verified by using animal models. To study the mechanism of Tcl1 regulation in CLL, we carried out microRNA expression profiling of three types of CLL: indolent CLL, aggressive CLL, and aggressive CLL showing 11q deletion. We identified distinct microRNA signatures corresponding to each group of CLL. We further determined that Tcl1 expression is regulated by miR-29 and miR-181, two microRNAs differentially expressed in CLL. Expression levels of miR-29 and miR-181 generally inversely correlated with Tcl1 expression in the CLL samples we examined. Our results suggest that Tcl1 expression in CLL is, at least in part, regulated by miR-29 and miR-181 and that these microRNAs may be candidates for therapeutic agents in CLLs overexpressing Tcl1.

Chromosome Deletion↗

PubMed2006

Multiplexing RT-PCR for the detection of multiple miRNA species in small samples.

MicroRNAs are short (approximately 22 nucleotides), non-coding RNAs that play critical roles in gene regulation and may be used as rapid precise diagnostic indicators of early stages of cancer. The small size of these RNAs makes detection of multiple microRNA species in very small samples problematic. Here we investigate the parameters associated with multiplexing RT-PCR to obtain relative abundance profiles of multiple microRNAs in small sample sizes down to the amount of RNA found in a single cell.

Humans↗

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↗

PubMed2006

Differential regulation of germline mRNAs in soma and germ cells by zebrafish miR-430.

Early in development, primordial germ cells (PGCs) are set aside from somatic cells and acquire a unique gene-expression program . The mechanisms underlying germline-specific gene expression are largely unknown. Nanos expression is required during germline development and is posttranscriptionally restricted to PGCs . Here we report that the microRNA miR-430 targets the 3' untranslated region (UTR) of nanos1 during zebrafish embryogenesis. A miR-430 target site within the nanos1 3' UTR reduces poly(A) tail length, mRNA stability, and translation. Repression is disrupted in maternal-zygotic dicer mutants (MZdicer), which lack mature miRNAs , and is restored by injection of processed miR-430. Although miR-430 represses other genes equally in germline and soma, specific regions in the nanos1 3' UTR compensate for microRNA-mediated repression in PGCs and allow germline-specific expression. We show that the 3' UTR of an additional PGC-specific gene, TDRD7, is also targeted by miR-430. These results indicate that miR-430 targets the 3' UTRs of germline genes and suggest that differential susceptibility to microRNAs contributes to tissue-specific gene expression.

3' Untranslated Regions↗

PubMed2026

miRNA-mediated control of TLR-NLR interplay in the uterus: A hidden corner of recurrent pregnancy loss.

Toll-like receptors (TLRs) and NOD-like receptors (NLRs) are crucial pattern recognition receptors that initiate inflammatory responses and immunological activation upon detecting pathogen- or damage-associated molecular patterns (PAMPs/DAMPS) in the female reproductive tract, thereby maintaining homeostasis and supporting pregnancy success. Their signaling pathways play a significant role in reproductive disorders by mediating the immune response to various pathogenic stimuli. Recurrent pregnancy loss (RPL), defined as the natural ending of two or more pregnancies before 24 weeks of gestation, approximately half of these patients remain idiopathic without precise prognostic, diagnostic, and therapeutic plans. Emerging data point that microRNAs are essential for immunological control in the female reproductive tract. MicroRNAs (miRNAs) are non-coding RNAs that regulate gene expression by binding to mRNA and preventing translation into protein. miRNAs play a role in many biological processes, including the development and differentiation of trophoblasts, the activation and implantation of embryos, immune tolerance, and the receptivity of the endometrium during implantation. Given their capacity to regulate up to 30 % of the human genome, miRNAs offer a promising avenue for understanding the immunopathogenesis of pregnancy complications. Recent research has detected differential expression of specific miRNAs in reproductive system pathologies. This review focuses on microRNAs and their association with idiopathic recurrent miscarriage, a condition characterized by considerable heterogeneity. Future studies identifying the precise mechanisms linking miRNA-mediated immune dysregulation in RPL immunopathogenesis could open the way for novel personalized therapeutic and diagnostic strategies.

Female↗

PubMed2006

Interaction of viruses with the mammalian RNA interference pathway.

It has been known for some time that plants and insects use RNA interference (RNAi) as nucleic acid-based immunity against viral infections. However, it was unknown whether mammalian cells employ the RNA interference pathway as an antiviral mechanism as well. Over the past years, it has become clear that a variety of viruses, first in plants but recently in insect and mammalian viruses as well, encode suppressors of the RNAi pathway arguing for an antiviral role of this machinery. More recent findings have revealed that certain viruses encode their own microRNAs or microRNA-like RNA molecules, which are processed by the mammalian RNAi machinery. Furthermore, host-encoded microRNAs have been shown to both silence and enhance intracellular levels of viral RNAs. These findings argue that interactions between the RNAi pathway and viral genomes can profoundly affect the outcomes of the viral life cycles and contribute to the pathogenic signatures of the infectious agents.

Animals↗

PubMed2003

Big things from a little RNA.

In a recent study, Brennecke and colleagues show that bantam, a previously elusive Drosophila gene that promotes tissue growth, encodes a microRNA. The bantam microRNA regulates cell number in vivo and inhibits cell death by binding to the mRNA of the pro-apoptotic gene hid. These findings demonstrate that a single, tiny Drosophila RNA can regulate organ and organism size and link the nascent field of microRNA function to the study of pathways that coordinate cell death, cell growth and cell proliferation during the development of metazoan organisms.

Animals↗

PubMed2025

Bioinformatic analyses and validated experiments reveal an aging hallmark gene set and protective miR of coronary artery disease.

To investigate how aging hallmarks exert roles in the age-related disease of coronary artery disease (CAD). R software and the GEO2R online tool identified differentially expressed genes (DEGs) and differentially expressed microRNAs (DEMis) in CAD microarray datasets from the Gene Expression Omnibus. Genes common to target genes of DEMis, DEGs, and an aging gene list from Human Aging Genomic Resources were then identified and analyzed for protein-protein interactions and functional and pathway enrichment. An miR-mRNA network was constructed using Cytoscape. Receiver operating characteristic curve analysis assessed the diagnostic utility of DEMis in CAD. The expression of two DEMis from a CAD cohort was employed to validate the findings. An aging hallmark gene set, comprising 18 genes, was delineated, with the hub gene TP53 established through protein-protein interaction and microRNA-mRNA networks. Within the microRNA-mRNA network, two DEMis (hsa-miR-423-5p and hsa-miR-564) potentially regulated TP53, rendering them potential CAD biomarkers, as indicated by their area under the curves (AUC) surpassing 0.6. Validation experiments corroborated an AUC of 0.7002 for hsa-miR-423-5p and 0.7261 for hsa-miR-564, highlighting its protective association with CAD. Combining hsa-miR-423-5p, hsa-miR-564, total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), white blood cells (WBC) achieved an area under the receiver operating characteristics curve of 0.783. A CAD-associated gene set was identified, with TP53 as the central hub. Hsa-miR-564 emerged as a potential protective factor against CAD.

Humans↗

PubMed2006

CRSD: a comprehensive web server for composite regulatory signature discovery.

Transcription factors (TFs) and microRNAs play important roles in the regulation of human gene expression, and the study of their combinatory regulations of gene expression is a new research field. We constructed a comprehensive web server, the composite regulatory signature database (CRSD), that can be applied in investigating complex regulatory behaviors involving gene expression signatures (GESs), microRNA regulatory signatures (MRSs) and TF regulatory signatures (TRSs). Six well-known and large-scale databases, including the human UniGene, mature microRNAs, putative promoter, TRANSFAC, pathway and Gene Ontology (GO) databases, were integrated to provide the comprehensive analysis in CRSD. Two new genome-wide databases, of MRSs and TRSs, were also constructed and further integrated into CRSD. To accomplish the microarray data analysis at one go, several methods, including microarray data pretreatment, statistical and clustering analysis, iterative enrichment analysis and motif discovery, were closely integrated in the web server, which has not been the case in previous studies. Our implementation showed that the published literature could demonstrate the results of genome-wide enrichment analysis. We conclude that CRSD is a powerful and useful bioinformatic web server and may provide new insights into gene regulation networks. CRSD and the online tutorial are publicly available at http://biochip.nchu.edu.tw/crsd1/.

3' Untranslated Regions↗

PubMed2004

Amphivasal vascular bundle 1, a gain-of-function mutation of the IFL1/REV gene, is associated with alterations in the polarity of leaves, stems and carpels.

In Arabidopsis stems, the vascular bundles in the stele are arranged in a ring-like pattern and the vascular tissues in each bundle are organized in a collateral pattern. We have shown previously that the semidominant amphivasal vascular bundle 1 (avb1) mutation transforms the collateral vascular bundles into amphivasal bundles and disrupts the ring-like arrangement of vascular bundles in the stele. In this study, we show that the avb1 mutation occurred in the putative microRNA 165 target sequence in the IFL1/REV gene and caused an amino acid substitution in the putative sterol/lipid-binding START domain. We present direct evidence that the wild-type IFL1/REV mRNA was cleaved within the microRNA 165 target sequence and the avb1 mutation resulted in an inhibition of cleavage and a higher level accumulation of full-length mRNA, suggesting a role of microRNA 165 in the regulation of IFL1/REV gene expression. In addition to an alteration in vascular patterning, the avb1 mutation also caused dramatic changes in fiber cell wall thickening and organ polarity, including aberrant formation and proliferation of cauline leaves and branches, production of trumpet-shaped leaves with reversed adaxial-abaxial identity, ectopic growth of carpel-like structures on the outer surface of carpels, and fasciation of inflorescence. Ectopic overexpression of the avb1 mutant cDNA not only phenocopied most of the avb1 mutant phenotypes but also led to additional novel phenotypes such as formation of leaves with extremely narrow blades and ectopic production of branches in the axil of siliques. Taken together, these results suggest that the avb1 gain-of-function mutation of the IFL1/REV gene alters the positional information that determines vascular patterning and organ polarity.

Amino Acid Sequence↗

PubMed2025

Investigating the miRNA-mRNA interactome of human trabecular meshwork cells treated with TGF-β1 provides insights into the pathogenesis of pseudoexfoliation glaucoma.

Pseudoexfoliation glaucoma is a severe form of secondary open angle glaucoma and is associated with activation of the TGF-β pathway by TGF-β1. MicroRNAs (miRNAs) are small non-coding RNA species that are involved in regulation of mRNA expression and translation. To investigate what glaucomatous changes occur in the trabecular meshwork and how these changes may be regulated by miRNAs, we performed a bioinformatics analysis resulting in a miRNA-mRNA interactome. Primary human trabecular meshwork cells originating from normal donors were treated with TGF-β1 at 5 ng/mL for 24h; total RNA was extracted followed by RNA-Seq and miRNA-Seq. For both mRNA and miRNA species, differential expression was determined using a bioinformatics pipeline consisting of FastQC, STAR, FeatureCounts, edgeR (for miRNA) and DESeq2 (for mRNA). Putative mRNA-miRNA interactions between differentially expressed mRNA and miRNA species were determined using interaction databases miRWalk, miRTarBase, TarBase and TargetScan. To classify mRNA species by function and pathway, gene enrichment was performed using Enrichr. The resulting miRNA-mRNA interactome consisted of 1202 interactions. Some highly connected microRNAs were hsa-let-7e-5p, hsa-miR-20a-5p, hsa-miR-122-5p, and hsa-miR-29c-3p. Most differentially expressed genes were indicated to be regulated by miRNAs. The sub-interactomes of genes involved in specific pseudoexfoliation glaucoma related enrichment terms such as oxidative stress, unfolded protein response, signal molecules and ECM remodelling were determined. This is the first study to present a genome-wide microRNA-mRNA regulatory network for human trabecular meshwork cells treated with TGF-β1 and may serve to generate unbiased hypotheses about regulatory functions and mRNA targets of miRNAs in pseudoexfoliation glaucoma and may help to develop miRNA-based therapeutics.

Humans↗

PubMed2025

Transcriptomic profile induced by calcitriol in CaSki human cervical cancer cell line.

The vitamin D endocrine system, primarily mediated by its main metabolite calcitriol and the vitamin D receptor (VDR), plays a critical role in numerous human physiological processes, ranging from calcium metabolism to the prevention of various tumors, including cervical cancer. In this study, we comprehensively investigated the genomic regulatory effects of calcitriol in a cervical cancer model. We examined the transcriptional changes induced by calcitriol in CaSki cells, a cervical cell line harboring multiple copies of HPV16, the primary causal agent of cervical cancer. Our microarray findings, revealed that calcitriol regulated over 1000 protein-coding genes, exhibiting a predominantly repressive effect on the CaSki cell transcriptome by suppressing twice as many genes as it induced. Calcitriol decreased EPHA2 and RARA expression while inducing KLK6 and CYP4F3 expression in CaSki cells, as validated by qPCR and Western blot. Functional analysis demonstrated that calcitriol effectively inhibited key processes involved in cancer progression, including cell proliferation and migration. This was further supported by the significant downregulation of MMP7 and MMP13 mRNA levels. Our microarray results also showed that, in addition to its effects on protein-coding genes, calcitriol significantly regulates non-coding RNAs, altering the expression of approximately 400 non-coding RNAs, including 111 microRNA precursors and 29 mature microRNAs, of which 17 were upregulated and 12 downregulated. Notably, among these calcitriol-regulated microRNAs are some involved in cervical cancer biology, such as miR-6129, miR-382, miR-655, miR-211, miR-590, miR-130a, miR-301a, and miR-1252. Collectively, these findings suggest that calcitriol exhibits a significant antitumor effect in this advanced cervical cancer model by blocking critical processes for tumor progression, underscoring the importance of maintaining adequate vitamin D nutritional status.

Humans↗

PubMed2004

Imprinted small RNA genes.

Genomic imprinting is an epigenetic phenomenon that results in differential expression of both alleles, depending on their parent of origin. We have recently identified many imprinted small non-coding RNA genes belonging to the C/D RNA and microRNA gene families, both of which are usually known to play key roles in post-transcriptional metabolism of specific genes (e.g. C/D RNAs guide ribose methylation of target RNAs while microRNAs elicit either translational repression or RNA interference). Although the functional and evolutionary significance of this association between C/D RNA genes, microRNA genes and genomic imprinting is still highly elusive, these observations provide a framework for further analysis of the potential role of small non-coding RNAs in epigenetic control.

Animals↗