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PubMed2026

Knowledge-driven interpretable neural networks provide mechanistic insight.

Analyzing omics data in the context of pathway knowledge is critical for understanding the molecular mechanisms underlying pathological changes. However, current pathway analysis methods do not model the detailed mechanistic nature of biological interactions, limiting the understanding of pathway behavior to a relatively shallow level. To address this issue, we present a knowledge-driven machine learning framework that embeds features into pathway graphs and models reactions analytically, producing interpretable feature hierarchies and subnetworks in which functional associations are estimated to model biological interactions. The approach is agnostic to feature selection, enabling the use of full omics data sets without discarding weak signals. Applications to breast cancer microRNA-gene regulation data and COVID-19 metabolomic data highlight immune and metabolic pathways relevant to disease progression. This framework bridges predictive modeling with mechanistic interpretation and offers a foundation for integrative pathway analysis.

Humans↗

PubMed2005

Computational prediction of miRNAs in Arabidopsis thaliana.

MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression in animals and plants. Comparative genomic computational methods have been developed to predict new miRNAs in worms, flies, and humans. Here, we present a novel single genome approach for the detection of miRNAs in Arabidopsis thaliana. This was initiated by producing a candidate miRNA-target data set using an algorithm called findMiRNA, which predicts potential miRNAs within candidate precursor sequences that have corresponding target sites within transcripts. From this data set, we used a characteristic divergence pattern of miRNA precursor families to select 13 potential new miRNAs for experimental verification, and found that corresponding small RNAs could be detected for at least eight of the candidate miRNAs. Expression of some of these miRNAs appears to be under developmental control. Our results are consistent with the idea that targets of miRNAs encompass a wide range of transcripts, including those for F-box factors, ubiquitin conjugases, Leucine-rich repeat proteins, and metabolic enzymes, and that regulation by miRNAs might be widespread in the genome. The entire set of annotated transcripts in the Arabidopsis genome has been run through find MiRNA to yield a data set that will enable identification of potential miRNAs directed against any target gene.

Algorithms↗

PubMed2005

Expression of Arabidopsis MIRNA genes.

MicroRNAs (miRNAs) are approximately 21-nucleotide noncoding RNAs that regulate target transcripts in plants and animals. In addition to miRNAs, plants contain several classes of endogenous small interfering RNAs (siRNAs) involved in target gene regulation and epigenetic silencing. Small RNA libraries were constructed from wild-type Arabidopsis (Arabidopsis thaliana) and mutant plants (rdr2 and dcl3) that were genetically enriched for miRNAs, and a computational procedure was developed to identify candidate miRNAs. Thirty-eight distinct miRNAs corresponding to 22 families were represented in the libraries. Using a 5' rapid amplification of cDNA ends procedure, the transcription start sites for 63 miRNA primary transcripts from 52 MIRNA loci (99 loci tested) were mapped, revealing features consistent with an RNA polymerase II mechanism of transcription. Ten loci (19%) yielded transcripts from multiple start sites. A canonical TATA box motif was identified upstream of the major start site at 45 (86%) of the mapped MIRNA loci. The 5'-mapping data were combined with miRNA cloning and 3'-PCR data to definitively validate expression of at least 73 MIRNA genes. These data provide a molecular basis to explore regulatory mechanisms of miRNA expression in plants.

Arabidopsis↗

PubMed2006

Characterization of 43 non-protein-coding mRNA genes in Arabidopsis, including the MIR162a-derived transcripts.

Messenger RNAs that do not contain a long open reading frame (ORF) or non-protein-coding RNAs (npcRNAs) are an emerging novel class of transcripts. Their functions may involve the RNA molecule itself and/or short ORF-encoded peptides. npcRNA genes are difficult to identify using standard gene prediction programs that rely on the presence of relatively long ORFs. Here, we used detailed bioinformatic analyses of expressed sequence tag/cDNA databases to detect a restricted set of npcRNAs in the Arabidopsis (Arabidopsis thaliana) genome and further characterized these transcripts using a combination of bioinformatic and molecular approaches. Compositional analyses revealed strong nucleotide strand asymmetries in the npcRNAs, as well as a biased GC content, suggesting the existence of functional constraints on these RNAs. Thirteen of these transcripts display tissue-specific expression patterns, and three are regulated in conditions affecting root architecture. The npcRNA 78 gene contains the miR162 sequence in an alternative intron and corresponds to the MIR162a locus. Although DICER-LIKE 1 (DCL1) mRNA is known to be regulated by miR162-guided cleavage, its level does not change in a mir162a mutant. Alternative splicing of npcRNA 78 leads to several transcript isoforms, which all accumulate in a dcl1 mutant. This suggests that npcRNA 78 is a genuine substrate of DCL1 and that splicing of this microRNA primary transcript and miR162 processing are competitive nuclear events. Our results provide new insights into Arabidopsis npcRNA biology and the potential roles of these genes.

Alternative Splicing↗

PubMed2006

PHO2, microRNA399, and PHR1 define a phosphate-signaling pathway in plants.

Inorganic phosphate (Pi)-signaling pathways in plants are still largely unknown. The Arabidopsis (Arabidopsis thaliana) pho2 mutant overaccumulates Pi in leaves in Pi-replete conditions. Micrografting revealed that a pho2 root genotype is sufficient to yield leaf Pi accumulation. In pho2 mutants, Pi does not repress a set of Pi starvation-induced genes, including AtIPS1, AT4, and Pi transporters Pht1;8 and Pht1;9. Map-based cloning identified PHO2 as At2g33770, an unusual E2 conjugase gene. It was recently shown that Pi deprivation induces mature microRNA (miRNA [miR399]) and that overexpression of miR399 in Pi-replete conditions represses E2 conjugase expression and leads to high leaf Pi concentrations, thus phenocopying pho2. We show here that miR399 primary transcripts are also strongly induced by low Pi and rapidly repressed after addition of Pi. PHO2 transcripts change reciprocally to miR399 transcripts in Pi-deprived plants and in miR399 overexpressers. However, responses after Pi readdition and in beta-glucuronidase reporter lines suggest that PHO2 expression is also regulated by Pi in a manner unrelated to miR399-mediated transcript cleavage. Expression of miR399 was strongly reduced in Pi-deprived Arabidopsis phr1 mutants, and a subset of Pi-responsive genes repressed in Pi-deprived phr1 mutants was up-regulated in Pi-replete pho2 mutants. This places miR399 and PHO2 in a branch of the Pi-signaling network downstream of PHR1. Finally, putative PHO2 orthologs containing five miR399-binding sites in their 5'-untranslated regions were identified in other higher plants, and Pi-dependent miR399 expression was demonstrated in rice (Oryza sativa), suggesting a conserved regulatory mechanism.

Arabidopsis↗

PubMed2006

Genomic organization, differential expression, and interaction of SQUAMOSA promoter-binding-like transcription factors and microRNA156 in rice.

Transcription factors play essential roles in the developmental processes of plants. Many such factors are regulated by microRNAs (miRNAs). SQUAMOSA (SQUA) promoter-binding-like (SPL) genes encode plant-specific transcription factors, some of which contain complementary sequences of miRNA156. In this study, 19 rice (Oryza sativa) SPL (OsSPL) genes and 12 rice miRNA156 (OsmiR156) precursors were identified in the rice genome. Sequence and experimental analysis suggested that 11 OsSPL genes were putative targets of OsmiR156. Plant SPL proteins were classified into six subgroups based on the phylogenetic analysis of SQUA promoter-binding protein domain. Diverse exon-intron structures and distinct organizations of putative motifs beyond the SQUA promoter-binding protein domains were identified in the OsSPL gene family. Transcript level analysis of OsSPL genes in various rice tissues and organs revealed different tempospatial expression patterns. More than half of the OsSPL genes including most OsmiR156-targeted genes are predominantly expressed in the young panicles, whereas OsmiR156 genes are predominantly expressed in the young shoots and leaves of rice. Overexpression of two OsmiR156 genes (OsmiR156b and OsmiR156h) in rice resulted in severe dwarfism, strongly reduced panicle size, and delayed flowering, suggesting that OsmiR156 and OsSPL target genes are involved in various developmental processes, especially the flower development of rice. Different patterns of transcript changes (decreased or unchanged) of different target genes in same tissue and of same target gene in different tissues detected in the OsmiR156-overexpressing plants suggested diverse interactions between OsmiR156 and OsSPL target genes in a tissue-specific manner.

Amino Acid Motifs↗

PubMed2004

A systemic small RNA signaling system in plants.

Systemic translocation of RNA exerts non-cell-autonomous control over plant development and defense. Long-distance delivery of mRNA has been proven, but transport of small interfering RNA and microRNA remains to be demonstrated. Analyses performed on phloem sap collected from a range of plants identified populations of small RNA species. The dynamic nature of this population was reflected in its response to growth conditions and viral infection. The authenticity of these phloem small RNA molecules was confirmed by bioinformatic analysis; potential targets for a set of phloem small RNA species were identified. Heterografting studies, using spontaneously silencing coat protein (CP) plant lines, also established that transgene-derived siRNA move in the long-distance phloem and initiate CP gene silencing in the scion. Biochemical analysis of pumpkin (Cucurbita maxima) phloem sap led to the characterization of C. maxima Phloem SMALL RNA BINDING PROTEIN1 (CmPSRP1), a unique component of the protein machinery probably involved in small RNA trafficking. Equivalently sized small RNA binding proteins were detected in phloem sap from cucumber (Cucumis sativus) and lupin (Lupinus albus). PSRP1 binds selectively to 25-nucleotide single-stranded RNA species. Microinjection studies provided direct evidence that PSRP1 could mediate the cell-to-cell trafficking of 25-nucleotide single-stranded, but not double-stranded, RNA molecules. The potential role played by PSRP1 in long-distance transmission of silencing signals is discussed with respect to the pathways and mechanisms used by plants to exert systemic control over developmental and physiological processes.

Amino Acid Sequence↗

PubMed2006

Posttranscriptional induction of two Cu/Zn superoxide dismutase genes in Arabidopsis is mediated by downregulation of miR398 and important for oxidative stress tolerance.

MicroRNAs (miRNAs) are a class of regulatory RNAs of approximately 21 nucleotides that posttranscriptionally regulate gene expression by directing mRNA cleavage or translational inhibition. Increasing evidence points to a potential role of miRNAs in diverse physiological processes. miR398 targets two closely related Cu/Zn superoxide dismutases (cytosolic CSD1 and chloroplastic CSD2) that can detoxify superoxide radicals. CSD1 and CSD2 transcripts are induced in response to oxidative stress, but the regulatory mechanism of the induction is unknown. Here, we show that miR398 expression is downregulated transcriptionally by oxidative stresses, and this downregulation is important for posttranscriptional CSD1 and CSD2 mRNA accumulation and oxidative stress tolerance. We also provide evidence for an important role of miR398 in specifying the spatial and temporal expression patterns of CSD1 and CSD2 mRNAs. Our results suggest that CSD1 and CSD2 expression is fine-tuned by miR398-directed mRNA cleavage. Additionally, we show that transgenic Arabidopsis thaliana plants overexpressing a miR398-resistant form of CSD2 accumulate more CSD2 mRNA than plants overexpressing a regular CSD2 and are consequently much more tolerant to high light, heavy metals, and other oxidative stresses. Thus, relieving miR398-guided suppression of CSD2 in transgenic plants is an effective new approach to improving plant productivity under oxidative stress conditions.

Arabidopsis↗

PubMed2006

The balance between the MIR164A and CUC2 genes controls leaf margin serration in Arabidopsis.

CUP-SHAPED COTYLEDON1 (CUC1), CUC2, and CUC3 define the boundary domain around organs in the Arabidopsis thaliana meristem. CUC1 and CUC2 transcripts are targeted by a microRNA (miRNA), miR164, encoded by MIR164A, B, and C. We show that each MIR164 is transcribed to generate a large population of primary miRNAs of variable size with a locally conserved secondary structure around the pre-miRNA. We identified mutations in the MIR164A gene that deepen serration of the leaf margin. By contrast, leaves of plants overexpressing miR164 have smooth margins. Enhanced leaf serration was observed following the expression of an miR164-resistant CUC2 but not of an miR164-resistant CUC1. Furthermore, CUC2 inactivation abolished serration in mir164a mutants and the wild type, whereas CUC1 inactivation did not. Thus, CUC2 specifically controls leaf margin development. CUC2 and MIR164A are transcribed in overlapping domains at the margins of young leaf primordia, with transcription gradually restricted to the sinus, where the leaf margins become serrated. We suggest that leaf margin development is controlled by a two-step process in Arabidopsis. The pattern of serration is determined first, independently of CUC2 and miR164. The balance between coexpressed CUC2 and MIR164A then determines the extent of serration.

Alleles↗

PubMed2007

ABA induction of miR159 controls transcript levels of two MYB factors during Arabidopsis seed germination.

Upon seed imbibition, abscisic acid (ABA) levels decrease to allow embryos to germinate and develop into seedlings. However, under abiotic stress conditions, ABA levels remain high, and growth and development are arrested. Several transcription factors, including abscisic acid-insensitive (ABI)3 and ABI5, are known to control this developmental checkpoint. Here, we show that, in germinating Arabidopsis thaliana seeds, ABA induces the accumulation of microRNA 159 (miR159) in an ABI3-dependent fashion, and miRNA159 mediates cleavage of MYB101 and MYB33 transcripts in vitro and in vivo. The two MYB transcription factors function as positive regulators of ABA responses, as null mutants of myb33 and myb101 show hyposensitivity to the hormone. Consistent with this, miR159 over-expression suppresses MYB33 and MYB101 transcript levels and renders plants hyposensitive to ABA, whereas transgenic plants over-expressing cleavage-resistant forms of MYB33 and MYB101 are hypersensitive, as are plants over-expressing the Turnip mosaic virus (TuMV) P1/HC-Pro viral protein that is known to inhibit miRNA function. Our results suggest that ABA-induced accumulation of miR159 is a homeostatic mechanism to direct MYB33 and MYB101 transcript degradation to desensitize hormone signaling during seedling stress responses.

Abscisic Acid↗

PubMed2005

Regulation of miRNA expression during neural cell specification.

MicroRNA (miRNA) are a newly recognized class of small, noncoding RNA molecules that participate in the developmental control of gene expression. We have studied the regulation of a set of highly expressed neural miRNA during mouse brain development. Temporal control is a characteristic of miRNA regulation in C. elegans and Drosophila, and is also prominent in the embryonic brain. We observed significant differences in the onset and magnitude of induction for individual miRNAs. Comparing expression in cultures of embryonic neurons and astrocytes we found marked lineage specificity for each of the miRNA in our study. Two of the most highly expressed miRNA in adult brain were preferentially expressed in neurons (mir-124, mir-128). In contrast, mir-23, a miRNA previously implicated in neural specification, was restricted to astrocytes. mir-26 and mir-29 were more strongly expressed in astrocytes than neurons, others were more evenly distributed (mir-9, mir-125). Lineage specificity was further explored using reporter constructs for two miRNA of particular interest (mir-125 and mir-128). miRNA-mediated suppression of both reporters was observed after transfection of the reporters into neurons but not astrocytes. miRNA were strongly induced during neural differentiation of embryonic stem cells, suggesting the validity of the stem cell model for studying miRNA regulation in neural development.

Animals↗

PubMed2006

Design of expression vectors for RNA interference based on miRNAs and RNA splicing.

RNA interference (RNAi) mediates sequence-specific post-transcriptional gene silencing in many eukaryotes and is used for reverse genetic studies and therapeutics. RNAi is triggered by double-stranded small interfering RNAs (siRNAs), which can be processed from small hairpin RNAs generated from an expression vector. In some recently described vectors, the siRNAs are expressed from synthetic stem-loop precursors of microRNAs (miRNAs) driven by polymerase II promoters. We have designed new RNAi vectors, designated pSM155 and pSM30, that take into consideration miRNA processing and RNA splicing by placing the miRNA-based artificial miRNA expression cassettes inside of synthetic introns. Like the original miRNA vectors, we show that the pSM155 and pSM30 constructs efficiently down-regulate expression of firefly luciferase and an endogenous gene, phospholipase D2. Moreover, the expression of a coexpressed fluorescent marker is substantially improved by this new design. Another improvement of these new vectors is incorporation of two inverted BsmBI sites placed internal to the arms of the new miRNA-based vectors, so oligos used for cloning are shorter and the cost is reduced. These RNAi vectors thus provide new tools for gene suppression.

Base Sequence↗

PubMed2026

A Novel Long Noncoding RNA-LNC000133 Associated With Steroid-Induced Osteonecrosis of the Femoral Head Promotes Osteoblast Differentiation Through Bone Marrow Mesenchymal Stem Cells-Derived Exosomes Pathway: A Bioinformatics Validation and Detailed Mechanistic Study.

Steroid-induced osteonecrosis of the femoral head (SONFH) is a debilitating disease caused by glucocorticoid abuse, characterized by complex pathogenesis and unclear molecular mechanisms. Dysfunction of bone marrow mesenchymal stem cells (BMSCs) and their exosome-mediated signalling is a key contributor to SONFH, although the precise mechanisms remain to be elucidated. In this study, the differential expression profiles of long noncoding RNAs (lncRNAs), microRNAs (miRNAs) and messenger RNAs (mRNAs) in exosomes derived from human BMSCs (hBMSCs) obtained from patients with SONFH compared to controls with femoral neck fractures were identified. Through next-generation sequencing, a novel lncRNA, LNC000133, associated with SONFH was discovered. Using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and competing endogenous RNA (ceRNA) network construction, the LNC000133/miR-362-5p/TGF-β3/SMAD3/BMP2 signalling axis was established. The definitive expression, localization and full-length sequence of LNC000133 in BMSCs were subsequently validated by Northern blot, quantitative real-time polymerase chain reaction (qRT-PCR), fluorescence in situ hybridization (FISH) and rapid amplification of cDNA ends (RACE). Most notably, mechanistic studies demonstrated that LNC000133-modified BMSCs-derived exosomes were efficiently taken up by osteoblasts, which promoted proliferation and osteogenic differentiation by targeting the miR-362-5p/TGF-β3/SMAD3/BMP2 signalling pathway.

Humans↗

PubMed2026

Integrative methylation and miRNA dysregulation in dlPFC reveal distinct molecular signatures of suicide and non-suicide subtypes in major depressive disorder.

AIM: Major depressive disorder (MDD) is a leading cause of disability and carries a high risk of suicide. MicroRNAs (miRNAs) are epigenetic regulators implicated in MDD and can be regulated by DNA methylation, potentially reshaping downstream gene networks. We investigated methylation-linked miRNA dysregulation and explored whether these changes are specifically associated with suicide among MDD patients. METHODS: Genome-wide DNA methylation profiling of the dorsolateral prefrontal cortex from 15 MDD patients who died by suicide (MDD+S), 17 MDD patients who died from causes other than suicide (MDD-S), and 16 controls (C) using the Illumina 850K MethylationEPIC array was integrated with small RNA sequencing-based miRNA quantification to identify miRNA-associated differentially methylated probes (DMPs), link methylation to miRNA expression, and infer downstream targets and pathways. RESULTS: Differential methylation analysis (P ≤ 0.05) revealed 139 miRNA-linked DMPs in C vs. MDD+/-S, 135 in C vs. MDD-S, 179 in C vs. MDD+S, and the highest in MDD+S vs. MDD-S (235). CpG-miRNA pairing (within 1500kb promoter) followed by Spearman correlation identified inverse associations between CpG β values and miRNA expression, with the most consistent signals in suicide-status-stratified subsets, including cg06341821-hsa-miR-574-3p and cg25451306-hsa-miR-2110 in MDD+S-related contrasts, and cg06179179-hsa-miR-595 in MDD-S-related contrasts. High-confidence target prediction and ClueGO enrichment indicated distinct biology: miR-595 target genes in MDD-S were enriched for interferon/innate immune signaling, whereas miR-2110 target genes in MDD+S were enriched for ligand-gated ion channel activity and synaptic/receptor signaling. CONCLUSION: This integrated approach identifies methylation-regulated miRNA pathways that may play key roles in the molecular pathogenesis of MDD and suicide.

Humans↗

PubMed2026

miR9772, a Triticum-specific miRNA involved in regulating wheat salt tolerance and grain size.

Salt stress severely impairs crop productivity worldwide. MicroRNAs (miRNAs) are a class of endogenous small noncoding RNAs, which played the crucial role in regulating plant growth, development as well as stress responses at the posttranscriptional level. However, the significance of miRNA on salt response in wheat is not well understood at present. In this study, we identified a salt-responsive miRNA from wild emmer wheat, miR9772, which appears to be specific to Triticum species. Under salt stress, the expression of miR9772 was significantly induced and upregulated. Functional analyses revealed that overexpression of miR9772 increased salt sensitivity in wheat, whereas silencing of miR9772 using Short Tandem Target Mimic (STTM) technology markedly enhanced salt tolerance, demonstrated its crucial role in regulating wheat's salt response. Furthermore, we revealed that miR9772 could target on CYP76C4 to decline its expression abundance to affect wheat's salt resistance. Additionally, agronomic and yield-related traits of transgenic wheat lines based on field experiments showed that miR9772-silenced lines exhibited larger grain size and higher grain yield per plant, indicating that miR9772 simultaneously regulated the salt tolerance and grain development. Collectively, this study provided a new target for improving wheat salt tolerance without yield penalty through genome editing breeding.

Triticum↗

PubMed2005

Ribo-gnome: the big world of small RNAs.

Small RNA guides--microRNAs, small interfering RNAs, and repeat-associated small interfering RNAs, 21 to 30 nucleotides in length--shape diverse cellular pathways, from chromosome architecture to stem cell maintenance. Fifteen years after the discovery of RNA silencing, we are only just beginning to understand the depth and complexity of how these RNAs regulate gene expression and to consider their role in shaping the evolutionary history of higher eukaryotes.

Animals↗

PubMed2005

Elucidation of the small RNA component of the transcriptome.

Small RNAs play important regulatory roles in most eukaryotes, but only a small proportion of these molecules have been identified. We sequenced more than two million small RNAs from seedlings and the inflorescence of the model plant Arabidopsis thaliana. Known and new microRNAs (miRNAs) were among the most abundant of the nonredundant set of more than 75,000 sequences, whereas more than half represented lower abundance small interfering RNAs (siRNAs) that match repetitive sequences, intergenic regions, and genes. Individual or clusters of highly regulated small RNAs were readily observed. Targets of antisense RNA or miRNA did not appear to be preferentially associated with siRNAs. Many genomic regions previously considered featureless were found to be sites of numerous small RNAs.

Arabidopsis↗

PubMed2005

It's a small RNA world, after all.

Small RNAs (sRNAs) can regulate transcript and protein abundance. Previously, they have been identified using traditional cloning approaches, which has limited how many could be characterized. Now, the Meyers and Green laboratories have used massively parallel signature sequencing technology to find over 1.5 million sRNAs in Arabidopsis thaliana. These new sRNAs reveal a greater-than-expected potential role for sRNAs in gene regulation, preferential expression or usage of sRNAs in flowers, and the prospect of targeted sRNA-mediated regulation of pseudogenes. In addition, new plant microRNAs have been identified, some of which may be unique to Arabidopsis.

Arabidopsis↗