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At least 1,207 records · Page 67Linked to original sources

PubMed2007

Qualitative network models and genome-wide expression data define carbon/nitrogen-responsive molecular machines in Arabidopsis.

BACKGROUND: Carbon (C) and nitrogen (N) metabolites can regulate gene expression in Arabidopsis thaliana. Here, we use multi-network analysis of microarray data to identify molecular networks regulated by C and N in the Arabidopsis root system. RESULTS: We used the Arabidopsis whole genome Affymetrix gene chip to explore global gene expression responses in plants exposed transiently to a matrix of C and N treatments. We used ANOVA analysis to define quantitative models of regulation for all detected genes. Our results suggest that about half of the Arabidopsis transcriptome is regulated by C, N or CN interactions. We found ample evidence for interactions between C and N that include genes involved in metabolic pathways, protein degradation and auxin signaling. To provide a global, yet detailed, view of how the cell molecular network is adjusted in response to the CN treatments, we constructed a qualitative multi-network model of the Arabidopsis metabolic and regulatory molecular network, including 6,176 genes, 1,459 metabolites and 230,900 interactions among them. We integrated the quantitative models of CN gene regulation with the wiring diagram in the multi-network, and identified specific interacting genes in biological modules that respond to C, N or CN treatments. CONCLUSION: Our results indicate that CN regulation occurs at multiple levels, including potential post-transcriptional control by microRNAs. The network analysis of our systematic dataset of CN treatments indicates that CN sensing is a mechanism that coordinates the global and coordinated regulation of specific sets of molecular machines in the plant cell.

Arabidopsis↗

PubMed2024

Small noncoding RNAs and sperm nuclear basic proteins reflect the environmental impact on germ cells.

BACKGROUND: Molecular techniques can complement conventional spermiogram analyses to provide new information on the fertilizing potential of spermatozoa and to identify early alterations due to environmental pollution. METHODS: Here, we present a multilevel molecular profiling by small RNA sequencing and sperm nuclear basic protein analysis of male germ cells from 33 healthy young subjects residing in low and high-polluted areas. RESULTS: Although sperm motility and sperm concentration were comparable between samples from the two sites, those from the high-pollution area had a higher concentration of immature/immune cells, a lower protamine/histone ratio, a reduced ability of sperm nuclear basic proteins to protect DNA from oxidative damage, and an altered copper/zinc ratio in sperm. Sperm levels of 32 microRNAs involved in intraflagellar transport, oxidative stress response, and spermatogenesis were different between the two areas. In parallel, a decrease of Piwi-interacting RNA levels was observed in samples from the high-polluted area. CONCLUSIONS: This comprehensive analysis provides new insights into pollution-driven epigenetic alterations in sperm not detectable by spermiogram.

Male↗

PubMed2024

Transcriptome-wide N6-methyladenosine modification profiling of long non-coding RNAs in patients with recurrent implantation failure.

N6-methyladenosine (m6A) is involved in most biological processes and actively participates in the regulation of reproduction. According to recent research, long non-coding RNAs (lncRNAs) and their m6A modifications are involved in reproductive diseases. In the present study, using m6A-modified RNA immunoprecipitation sequencing (m6A-seq), we established the m6A methylation transcription profiles in patients with recurrent implantation failure (RIF) for the first time. There were 1443 significantly upregulated m6A peaks and 425 significantly downregulated m6A peaks in RIF. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed that genes associated with differentially methylated lncRNAs are involved in the p53 signalling pathway and amino acid metabolism. The competing endogenous RNA network revealed a regulatory relationship between lncRNAs, microRNAs and messenger RNAs. We verified the m6A methylation abundances of lncRNAs by using m6A-RNA immunoprecipitation (MeRIP)-real-time polymerase chain reaction. This study lays a foundation for further exploration of the potential role of m6A modification in the pathogenesis of RIF.

Humans↗

PubMed2005

Recognition of chromosomal DNA in human cells by peptide nucleic acids and small duplex RNAs.

Inhibition of translation by duplex RNA (siRNA) complementary to mRNA is a powerful approach to silencing genes in mammalian cells and RNA interference (RNAi) is an important natural biological mechanism for controlling gene expression. Anti-mRNA duplexes are widely used for laboratory studies, target validation, and therapeutic development. Endogenously expressed duplex RNAs (microRNAs, miRNAs) have been shown to target mRNA and be natural regulators of expression. Recently, we have shown that peptide nucleic acids (PNAs) or duplex antigene RNAs (agRNAs) that target DNA sequences can also inhibit gene transcription. These findings extend gene silencing to targets within chromosomal DNA.

Alternative Splicing↗

PubMed2006

Differential regulation of imprinting in the murine embryo and placenta by the Dlk1-Dio3 imprinting control region.

Genomic imprinting is an epigenetic mechanism controlling parental-origin-specific gene expression. Perturbing the parental origin of the distal portion of mouse chromosome 12 causes alterations in the dosage of imprinted genes resulting in embryonic lethality and developmental abnormalities of both embryo and placenta. A 1 Mb imprinted domain identified on distal chromosome 12 contains three paternally expressed protein-coding genes and multiple non-coding RNA genes, including snoRNAs and microRNAs, expressed from the maternally inherited chromosome. An intergenic, parental-origin-specific differentially methylated region, the IG-DMR, which is unmethylated on the maternally inherited chromosome, is necessary for the repression of the paternally expressed protein-coding genes and for activation of the maternally expressed non-coding RNAs: its absence causes the maternal chromosome to behave like the paternally inherited one. Here, we characterise the developmental consequences of this epigenotype switch and compare these with phenotypes associated with paternal uniparental disomy of mouse chromosome 12. The results show that the embryonic defects described for uniparental disomy embryos can be attributed to this one cluster of imprinted genes on distal chromosome 12 and that these defects alone, and not the mutant placenta, can cause prenatal lethality. In the placenta, the absence of the IG-DMR has no phenotypic consequence. Loss of repression of the protein-coding genes occurs but the non-coding RNAs are not repressed on the maternally inherited chromosome. This indicates that the mechanism of action of the IG-DMR is different in the embryo and the placenta and suggests that the epigenetic control of imprinting differs in these two lineages.

Animals↗

PubMed2005

Human mitochondrial tRNAMet is exported to the cytoplasm and associates with the Argonaute 2 protein.

Argonaute (Ago) proteins are the effector proteins of RNA interference (RNAi) and related silencing mechanisms that are mediated by small RNAs. Ago proteins bind directly to microRNAs (miRNAs) and to short interfering RNAs and are the core protein components of RNA induced silencing complexes (RISCs) and microRNPs (miRNPs). Here we report that an ~70-nt RNA associates specifically with immunopurified Ago2 expressed in human 293 cells. By directional cloning we identified this RNA as the mitochondrial tRNA(Met) (mt tRNA(Met)). Various exported (mt) tRNAs were detected in the cytosol of 293 cells, but Ago2 was found selectively bound to (mt) tRNA(Met). The association in the cytosol of exported (mt) tRNA(Met) with Ago2 complements genetic and microscopic data that link mitochondria with RNAi-related components and events.

Active Transport, Cell Nucleus↗

PubMed2006

Interacting endogenous and exogenous RNAi pathways in Caenorhabditis elegans.

C. elegans contains numerous small RNAs of ~21-24 nt in length. The microRNAs (miRNAs) are small noncoding RNAs produced by DCR-1- and ALG-dependent processing of self-complementary hairpin transcripts. Endogenous small interfering RNAs (endo-siRNAs), associated with ongoing silencing of protein-coding genes in normal worms, are produced by mechanisms that involve DCR-1 but, unlike miRNAs, also involve RDE-2, RDE-3, RDE-4, RRF-1, and RRF-3. The tiny noncoding (tncRNAs) are similar to endo-siRNAs in their biogenesis except that they are derived from noncoding sequences. These endo-siRNA- and tncRNA-based endogenous RNAi pathways involve some components, including DCR-1 and RDE-4, that are shared with exogenous RNAi, and some components, including RRF-3 and ERI-1, that are specific to endogenous RNAi. rrf-3 and eri-1 mutants are enhanced for some silencing processes and defective for others, suggesting cross-regulatory interactions between RNAi pathways in C. elegans. Microarray expression profiling of RNAi-defective mutant worms further suggests diverse endogenous RNAi pathways for silencing different sets of genes.

Animals↗

PubMed2005

Sorghum genome sequencing by methylation filtration.

Sorghum bicolor is a close relative of maize and is a staple crop in Africa and much of the developing world because of its superior tolerance of arid growth conditions. We have generated sequence from the hypomethylated portion of the sorghum genome by applying methylation filtration (MF) technology. The evidence suggests that 96% of the genes have been sequence tagged, with an average coverage of 65% across their length. Remarkably, this level of gene discovery was accomplished after generating a raw coverage of less than 300 megabases of the 735-megabase genome. MF preferentially captures exons and introns, promoters, microRNAs, and simple sequence repeats, and minimizes interspersed repeats, thus providing a robust view of the functional parts of the genome. The sorghum MF sequence set is beneficial to research on sorghum and is also a powerful resource for comparative genomics among the grasses and across the entire plant kingdom. Thousands of hypothetical gene predictions in rice and Arabidopsis are supported by the sorghum dataset, and genomic similarities highlight evolutionarily conserved regions that will lead to a better understanding of rice and Arabidopsis.

Arabidopsis↗

PubMed2006

Overlapping functions of argonaute proteins in patterning and morphogenesis of Drosophila embryos.

Argonaute proteins are essential components of the molecular machinery that drives RNA silencing. In Drosophila, different members of the Argonaute family of proteins have been assigned to distinct RNA silencing pathways. While Ago1 is required for microRNA function, Ago2 is a crucial component of the RNA-induced silencing complex in siRNA-triggered RNA interference. Drosophila Ago2 contains an unusual amino-terminus with two types of imperfect glutamine-rich repeats (GRRs) of unknown function. Here we show that the GRRs of Ago2 are essential for the normal function of the protein. Alleles with reduced numbers of GRRs cause specific disruptions in two morphogenetic processes associated with the midblastula transition: membrane growth and microtubule-based organelle transport. These defects do not appear to result from disruption of siRNA-dependent processes but rather suggest an interference of the mutant Ago2 proteins in an Ago1-dependent pathway. Using loss-of-function alleles, we further demonstrate that Ago1 and Ago2 act in a partially redundant manner to control the expression of the segment-polarity gene wingless in the early embryo. Our findings argue against a strict separation of Ago1 and Ago2 functions and suggest that these proteins act in concert to control key steps of the midblastula transition and of segmental patterning.

Animals↗

PubMed2004

Induction and biochemical purification of RNA-induced silencing complex from Drosophila S2 cells.

The discovery of RNA interference (RNAi) has greatly simplified the process of suppressing genes in many experimental systems, including Caenorhabditis elegans, Drosophila, and mammalian cells. A sequence-specific nuclease complex, called the RNA-induced silencing complex (RISC), can be purified from cells undergoing RNAi. RISC shows RNase activity when exposed to RNAs homologous to the input double-stranded RNA (dsRNAs) but lacks activity in the presence of nontargeted RNAs. We describe the induction of RNAi by dsRNA in cultured Drosophila Schneider-2 (S2) cells and detail procedures for RISC purification from these cells. This purification approach has allowed us to identify several RISC components, including siRNAs, Argo naute 2 (Ago-2), Drosophila Fragile X related protein (dFXR), Vasa intronic gene (VIG), and the micrococcal nuclease family member Tudor-SN (Drosophila CG7008). RNAi is carried out by an endogenous pathway important for normal development in many organisms. In fact, organisms express hundreds of different microRNAs (miRNAs), small hairpin RNAs that function through the RNAi pathway to suppress expression of endogenous genes. The function of miRNAs is poorly understood, and most of their targets are unknown. Purified RISC complexes contain short interfering RNAs and endogenously expressed miRNAs and will be useful for studying many aspects of the RNAi machinery.

Animals↗

PubMed2004

Intravenous, non-viral RNAi gene therapy of brain cancer.

RNA interference (RNAi) has the potential to knock down oncogenes in cancer, including brain cancer. However, the therapeutic potential of RNAi will not be realised until the rate-limiting step of delivery is solved. The development of RNA-based therapeutics is not practical, due to the instability of RNA in vivo. However, plasmid DNA can be engineered to express short hairpin RNA (shRNA), similar to endogenous microRNAs. Intravenous, non-viral RNAi-based gene therapy is enabled with a new gene-targeting technology, which encapsulates the plasmid DNA inside receptor-specific pegylated immunoliposomes (PILs). The feasibility of this RNAi approach was evaluated by showing it was possible to achieve a 90% knockdown of brain tumour-specific gene expression with a single intravenous injection in adult rats or mice with intracranial brain cancer. The survival of mice with intracranial human brain cancer was extended by nearly 90% with weekly intravenous injections of PILs carrying plasmid DNA expressing a shRNA directed against the human epidermal growth factor receptor. RNAi-based gene therapy can be coupled with gene therapy that replaces mutated tumour suppressor genes to build a polygenic approach to the gene therapy of cancer.

Animals↗

PubMed2005

12th annual congress of the European Society of Gene Therapy.

The 2004 European Society of Gene Therapy (ESGT) meeting took place at Tampere Hall in Finland and highlighted advances in a variety of topics, including cancer, zinc-fingers, stem cells, small interfering RNA (siRNA), microRNA, and recent developments of non-viral and viral vectors. This meeting was attended by 513 participants from 32 countries, and included 106 oral and 224 poster presentations. One of the aims of this meeting was to take a critical look at gene therapy and the prospects for the future. Se-veral presentations reported on RNA-based technologies, such as siRNA, as potential new classes of therapeutics against a wide range of diseases and for use in expression libraries to identify functional genes involved in biological phenotypes. Critical assessments were made of other aspects of gene therapy, such as genome editing and the use of protein transduction domains (PTDs) in gene- and protein-based therapies, where many researchers have failed to reproduce initial findings reported in the literature. Safety issues related to viral vectors were also important areas of discussion, especially following details released by the UK Gene Therapy Advisory Committee of perhaps the first known case of lentiviral vector-associated oncogenesis. Finally, updates were presented on the clinical development of viral vectors in anticancer therapies with evidence of significant improvements in the mean survival of patients.

Clinical Trials as Topic↗

PubMed2005

RNAi as an antiviral therapy.

There are a dozen or so viruses that will continue to be a serious global health threat for many years to come, mainly due to their chronic nature. These include hepatitis C virus (HCV), human papillomavirus viruses (HPVs), West Nile virus and human herpes viruses (i.e., HSV, CMV, EBV, HHV-8, etc.). However, HIV-1 infections will remain at the top of the list due to its high prevalence and the significant mortality and morbidity from AIDS. The development of a suitable vaccine against HIV-1 remains an important area of public interest. The initial hope of identifying the specific anti-HIV-1 antigenic epitopes that can protect HIV-1-infected individuals and serve as a potential vaccine has been replaced by the realisation that we have yet to identify a clear correlation of protective immunity against HIV-1 infection. Understanding the anti-HIV-1 protective factors and their potential role in the development of a vaccine or inexpensive therapy remains one of the major obstacles in HIV-1 research. In the last quarter century--since the realisation of AIDS--previous studies have established that the role of humoral or cellular immune responses in protecting human hosts against HIV-1 have been inconclusive. Moreover, most of the publicized and awaited clinical trials on vaccines have failed. The recent discovery of RNA interference (RNAi) has raised the possibility of developing a new generation of vaccines that can stymie human viruses, particularly HIV-1 replication at various stages of its life cycle at the intracellular level. Various transcripts in the HIV-1 life cycle can be targeted, and specific small double-stranded RNAs (small interfering RNAs) can be developed against these HIV-1-specific targets. However, some recent data suggests that RNAi-based therapeutics against this virus should be viewed with strong caution. Specifically, there are multiple factors that make HIV-1 a difficult infection to 'cure' because of HIV-1 latency. The changing nature of HIV-1 genomes and the possible presence of microRNAs within the HIV-1 genes can suppress RNAi directed against HIV-1 gene targets. Thus, HIV-1 would be a difficult epidemic to overcome by RNAi-based therapeutics.

Animals↗

PubMed2026

An overview of the DNA damage response in female reproductive system and breast cancers: A narrative review.

The DNA damage response (DDR) is a fundamental cellular network that preserves genomic integrity, and its dysregulation drives initiation, progression, and therapeutic response in female reproductive system and breast cancers. This narrative review provides a comparative analysis of DDR alterations across ovarian, endometrial, cervical, and breast cancers, synthesizing molecular studies, clinical trials, and international guidelines from PubMed/MEDLINE, Scopus, and Web of Science. DDR alterations vary substantially among these cancers, reflecting differences in tissue origin, hormonal regulation, and viral oncogenesis. Homologous recombination repair defects, particularly in breast cancer susceptibility 1/2, partner and localizer of BRCA2, ataxia telangiectasia mutated, and checkpoint kinase 2), are prevalent in ovarian, endometrial, and breast cancers, predicting sensitivity to platinum-based chemotherapy and poly (ADP-ribose) polymerase inhibitors. In endometrial cancer, homologous recombination deficiency predominates in high-grade tumor protein p53-mutated subtypes, while Fanconi anemia pathway alterations characterize aggressive serous carcinomas. Cervical cancer exhibits virus-induced DDR disruption and replication stress. Quantitative biomarkers, including tumor mutational burden, microsatellite instability, Radiation sensitive 51, Fanconi anemia complementation group D2, excision repair cross-complementation group 1, and DDR-related microRNAs enable patient stratification. Emerging ataxia telangiectasia and Rad3-related and WEE1 inhibitors show promise in combination regimens. Understanding of tumor-specific DDR enables rational therapeutic stratification, providing a framework for precision oncology.

DNA damage response, Ovarian neoplasms, Endometria↗

PubMed2025

Expression of long noncoding RNAs in peripheral blood mononuclear cells of patients with type 1 diabetes mellitus: potential biomarkers for disease onset.

OBJECTIVE: Long non-coding RNAs (lncRNAs) do not encode proteins and are transcripts longer than 200 nucleotides. The precise involvement of lncRNAs in type 1 diabetes mellitus (T1DM) pathogenesis remains unclear. Therefore, this study aimed to analyze the expressions of five lncRNAs in peripheral blood mononuclear cells of individuals with T1DM and without DM. MATERIALS AND METHODS: This study comprised 27 patients with T1DM (cases) and 13 individuals without DM (controls). The case group was divided into two subgroups based on T1DM duration: < 5 years of diagnosis group and long-term diabetes group (≥5 years). LncRNA expression was evaluated by qPCR. RESULTS: MALAT1 and TUG1 were upregulated in patients within the first five years of diagnosis of T1DM compared to the other groups. MEG3 was upregulated in the case group of < 5 years of diagnosis compared to controls. TUG1 and MALAT1 levels were negatively correlated with the duration of T1DM, while TUG1 and MEG3 were positively correlated with glycated hemoglobin levels. Bioinformatics analysis revealed that MALAT1, MEG3, and TUG1 regulate and interact with protein-codifying genes and microRNAs involved in T1DM-related pathways. CONCLUSION: Our study revealed MALAT1, MEG3, and TUG1 upregulation in patients within the first five years of diagnosis of T1DM.

Humans↗

PubMed2005

RNA splicing manipulation: strategies to modify gene expression for a variety of therapeutic outcomes.

Antisense oligonucleotides initially offered great hope as specific compounds to modify gene expression, primarily through RNaseH induced degradation of the target transcript. Expansion of the field led to new chemistries capable of invoking different mechanisms, including suppression of protein synthesis by translational blockade, and there is now a major interest in downregulation of gene expression using short interfering RNAs to induce RNA silencing. Naturally occurring microRNAs have been implicated in the regulation of gene expression. This review considers examples of antisense oligonucleotides redirecting the process of exon recognition and intron removal during gene transcript splicing. While suppression of gene expression is necessary to address some conditions, it appears likely that there may be many more clinical applications for antisense oligonucleotides in re-directing splicing patterns. Pre-mRNA splicing is a tightly co-ordinated, multifactorial process, which can be disrupted by antisense oligonucleotides in a highly specific manner, allowing either suppression of aberrant splicing, by-pass of nonsense or frame-shifting mutations or alteration of spliceoform ratios. Manipulation of splicing patterns has been applied to a diverse range of conditions, including beta-thalassemia, Duchenne muscular dystrophy, spinal muscular atrophy and certain cancers. Alternative exon usage has been identified as a major mechanism for generating diversity from a limited repertoire of genes in higher eukaryotes. Considering that up to 75% of all human primary gene transcripts are reported to be alternatively spliced, intervention at the level of pre-mRNA processing is likely to become increasingly significant in the fight against genetic and acquired disorders.

Alternative Splicing↗

PubMed2005

An introduction to RNA-mediated gene silencing.

Careful analysis of cases where introduction of additional copies of endogenous genes caused coordinate silencing of both the transgene and the endogenous gene laid the ground work for the discovery of RNA-mediated silencing. Silencing begins with the expression and recognition of double-stranded RNA, which is cleaved into short RNAs that recognize, by complementarity, sequences that are targets for down regulation. An RNA target can be regarded (post-transcriptional gene silencing), but the small RNAs can also direct the sequence-specific modification of DNA and chromatin. RNA-mediated gene silencing in eukaryotes may have originated as surveillance mechanism to protect the organism from transposable elements and viruses and then evolved to specify chromosomal modifications and to regulate expression of a significant fraction of endogenous genes by microRNAs. This review seeks to furnish the student and non-expert with some idea of how RNA-mediated silencing was discovered and a broad overview of the present state of knowledge.

Animals↗

PubMed2026

Freely available genomic datasets for atrial fibrillation research: current resources and analytical pipeline.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, characterized by clinical and genetic heterogeneity. Increasing use of genomics and other omics approaches has driven reliance on publicly available AF datasets to advance biological discovery. Thus, this systematic review aimed to identify freely available genomic AF datasets through Mendeley Data and its interconnected repositories, and to characterize the most common analyses performed on these data. The search was conducted in adherence to the PRISMA 2020 guideline. Nineteen freely available genomic AF datasets were identified: Summary statistics for 'Biobank-driven genomic discovery yields new insight into atrial fibrillation biology', hum0014.v8.58qt.v1, AF GWAS in UK Biobank, UK Biobank (Publication 9659), GWAS summary statistics from a 2025 multi-ancestry AF meta-analysis, GSE115574, GSE128188, GSE14975, GSE2240, GSE238242, GSE254133, GSE261170, GSE271748, GSE271839, GSE293813, GSE294456, GSE31821, GSE41177, and GSE79768. The GEO datasets were further examined using differential gene expression, functional enrichment, protein-protein interaction networks, hub gene analysis, microRNA target prediction, and gene clustering, as well as, for the more recently deposited datasets, eQTL colocalization, single-cell/single-nucleus clustering, cell-cell communication analysis, and gene-dosage-dependent transcriptional and electrophysiological profiling. These analyses show some consistency but also considerable heterogeneity in initial conditions, data normalization, and analytical methodological settings. In conclusion, only a limited number of datasets are freely available, so additional, well-characterized and standardized datasets are needed to provide a complete picture of the AF pathology.

Mendeley Data↗