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PubMed2006

Repetitive elements in imprinted genes.

Genomic imprinting in mammals results in mono-allelic expression of about 80 genes depending on the parental origin of the alleles. Though the epigenetic mechanisms underlying imprinting are rather clear, little is known about the genetic basis for these epigenetic mechanisms. It is still rather enigmatic which sequence features discriminate imprinted from non-imprinted genes/regions and why and how certain sequence elements are recognized and differentially marked in the germlines. It seems likely that specific DNA elements serve as signatures that guide the necessary epigenetic modification machineries to the imprinted regions. Inter- and intraspecific comparative genomic studies suggest that the unusual occurrence and distribution of various types of repetitive elements within imprinted regions may represent such genomic imprinting signatures. In this review we summarize the various observations made and discuss them in light of experimental data.

Animals↗
PubMed2006

The imprinted mouse Igf2r/Air cluster--a model maternal imprinting system.

Every diploid organism inherits a complete chromosome set from its father and mother in addition to the sex chromosomes, so that all autosomal genes are available in two copies. For most genes, both copies are expressed without preference. Imprinted genes, however, are expressed depending on their parental origin, being active on the paternal or maternal allele only. To date 73 imprinted genes are known in mouse (www.mgu.har.mrc.ac.uk/research/imprinting), 37 show paternal expression while 36 show maternal expression, indicating no bias for imprinting to occur in one sex or the other. Therefore, two different parental-specific imprinting systems may have evolved in mammals, acting specifically in the paternal or maternal gamete. Similarities and differences between the two imprinting systems will be reviewed, with specific reference to the role of non-coding RNAs and chromatin modifications. The mouse Igf2r/Air cluster is presented as a model of the maternal imprinting system.

Animals↗
PubMed2026

UHRF1 deficiency exacerbates intestinal inflammation by epigenetic modulation of NPY1R gene methylation.

Epigenetic modifications play a crucial role in the pathogenesis of inflammatory bowel disease (IBD) by mediating gene-environment interactions. We previously showed that UHRF1, a central regulator of DNA methylation, contributes to cancer progression; however, its function in IBD remains poorly understood. Here, we revealed that UHRF1 was frequently reduced in inflamed tissues of patients with IBD and that its deficiency exacerbated intestinal epithelial cell (IEC) damage. Through a multilevel approach incorporating human cell models and an intestinal epithelial-specific Uhrf1-KO mouse model, we established UHRF1 as a key mitigator of IBD progression. Mechanistically, UHRF1 bound to the NPY1R promoter, promoted its methylation, and led to transcriptional suppression. The NPY1R upregulation resulting from UHRF1 deficiency attenuated cAMP/PKA/CREB signaling in IECs, thereby enhancing NF-κB activation and subsequent proinflammatory responses, which compromised intestinal epithelial barrier integrity. Furthermore, we identified miR-141 as a negative regulator of NPY1R, highlighting its potential as a therapeutic agent. Collectively, our results identified the UHRF1/NPY1R regulatory axis as a critical epigenetic mechanism in intestinal inflammation and underscored its dual promise for IBD diagnostics and therapy.

Animals↗
PubMed2026

Extracellular vesicle miR-93-5p cargo regulates glomerular endothelial cell damage in Alport syndrome.

Modulation of miRNA expression in glomerular cells is associated with renal disease. Here, we investigated the role of miR-93-5p in mitigating glomerular damage in Alport syndrome and whether the disease-modifying activity of extracellular vesicles from human amniotic fluid stem cells (hAFSC-EVs) is mediated by their miR-93-5p cargo. We identified downregulation of miR-93-5p specifically in glomerular endothelial cells in Alport syndrome along disease progression. Silencing of miR-93-5p in hAFSC-EVs changed the transcriptomic and proteomic profile, regulating EV disease-modifying activity. Compared with naive hAFSC-EVs, silenced hAFSC-EVs did not rescue glomerular endothelial function in vitro and did not restore kidney function in vivo. We established that hAFSC-EVs regulate VEGFR1 and VEGFR2 signaling by miR-93-5p cargo transfer, highlighting that miR-93-5p can restore glomerular endothelial cell biology. Spatial transcriptomics analysis of hAFSC-EV-injected kidneys showed that these EVs can reverse pathways altered during disease progression by stimulating proregenerative processes, specifically in the glomerulus, by regulating miR-93-5p targets. Alteration of glomerular endothelial cell transcriptomics and miR-93-5p targets was also confirmed in biopsies of patients with Alport syndrome using spatial molecular imaging. We demonstrated the critical role of miR-93-5p in glomerular endothelial cells and the capability of hAFSC-EVs to regulate miR-93-5p and its targets in Alport syndrome.

Humans↗
PubMed2026

Tracing the molecular route to progression in miRNA-biogenesis-defective thyroid lesions.

Germline and somatic changes in DICER1 and DGCR8 microprocessors confer risk of developing benign and malignant thyroid lesions, yet the molecular events driving malignant transformation remain unclear. We trace the molecular trajectories from benignity to malignancy in DICER1- and DGCR8-mutated thyroid lesions using multiomic profiling on over 30 DICER1-/DGCR8-mutated samples. Our findings reveal a progressive, specific, and linear accumulation of genetic changes, which when combined with enhanced downregulation of miRNAs distinguished DICER1-/DGCR8-malignant lesions from their benign counterparts. Compensatory hypomethylation of miRNA-encoding genes characterized DICER1-/DGCR8-benign lesions, but as the tumors progressed to malignancy, methylation was partly reimposed, reversing the attempts to activate miRNA-encoded genes and further compromising miRNA production. Transcriptomic analyses revealed mutation-specific effects on the microenvironment, whereby DICER1 mutations activated canonical thyroid cancer progression pathways, whereas altered DGCR8 associated with immune-related changes. This work unveils specific molecular events underlying malignant progression of miRNA-biogenesis-related thyroid tumors and identifies potential biomarkers and disease etiology mechanisms.

MicroRNAs↗
PubMed2006

RNAi based approaches to the treatment of malignant glioma.

RNA interference (RNAi) is a recently discovered, powerful molecular mechanism that can be harnessed to engineer gene-specific silencing in mammalian tissues. A mechanism, where short double-stranded RNA (dsRNA) molecules, when introduced into cells elicit specific "knock-down" of gene expression via degradation of targeted messenger RNA, has lately become the technique of choice for analysis of gene function in oncology research. Thus, RNAi is currently being extensively evaluated as a potential therapeutic strategy against malignant gliomas, since surgical, radiological, and chemotherapeutic interventions during the past few decades have done little to improve the poor prognosis rate for patients with these dreaded tumors. This review summarizes the pre-clinical studies that are currently underway to test the validity of RNAi as a potential therapeutic strategy against malignant gliomas, and discusses the potential technical hurdles that remain to be overcome before the technique can become a promising clinical therapy to combat this frequently lethal disease.

Animals↗
PubMed2003

RSEARCH: finding homologs of single structured RNA sequences.

BACKGROUND: For many RNA molecules, secondary structure rather than primary sequence is the evolutionarily conserved feature. No programs have yet been published that allow searching a sequence database for homologs of a single RNA molecule on the basis of secondary structure. RESULTS: We have developed a program, RSEARCH, that takes a single RNA sequence with its secondary structure and utilizes a local alignment algorithm to search a database for homologous RNAs. For this purpose, we have developed a series of base pair and single nucleotide substitution matrices for RNA sequences called RIBOSUM matrices. RSEARCH reports the statistical confidence for each hit as well as the structural alignment of the hit. We show several examples in which RSEARCH outperforms the primary sequence search programs BLAST and SSEARCH. The primary drawback of the program is that it is slow. The C code for RSEARCH is freely available from our lab's website. CONCLUSION: RSEARCH outperforms primary sequence programs in finding homologs of structured RNA sequences.

Animals↗
PubMed2006

RDMAS: a web server for RNA deleterious mutation analysis.

BACKGROUND: The diverse functions of ncRNAs critically depend on their structures. Mutations in ncRNAs disrupting the structures of functional sites are expected to be deleterious. RNA deleterious mutations have attracted wide attentions because some of them in cells result in serious disease, and some others in microbes influence their fitness. RESULTS: The RDMAS web server we describe here is an online tool for evaluating structural deleteriousness of single nucleotide mutation in RNA genes. Several structure comparison methods have been integrated; sub-optimal structures predicted can be optionally involved to mitigate the uncertainty of secondary structure prediction. With a user-friendly interface, the web application is easy to use. Intuitive illustrations are provided along with the original computational results to facilitate quick analysis. CONCLUSION: RDMAS can be used to explore the structure alterations which cause mutations pathogenic, and to predict deleterious mutations which may help to determine the functionally critical regions. RDMAS is freely accessed via http://biosrv1.bmi.ac.cn/rdmas.

Databases, Nucleic Acid↗
PubMed2004

How many novel eukaryotic 'kingdoms'? Pitfalls and limitations of environmental DNA surveys.

BACKGROUND: Over the past few years, the use of molecular techniques to detect cultivation-independent, eukaryotic diversity has proven to be a powerful approach. Based on small-subunit ribosomal RNA (SSU rRNA) gene analyses, these studies have revealed the existence of an unexpected variety of new phylotypes. Some of them represent novel diversity in known eukaryotic groups, mainly stramenopiles and alveolates. Others do not seem to be related to any molecularly described lineage, and have been proposed to represent novel eukaryotic kingdoms. In order to review the evolutionary importance of this novel high-level eukaryotic diversity critically, and to test the potential technical and analytical pitfalls and limitations of eukaryotic environmental DNA surveys (EES), we analysed 484 environmental SSU rRNA gene sequences, including 81 new sequences from sediments of the small river, the Seymaz (Geneva, Switzerland). RESULTS: Based on a detailed screening of an exhaustive alignment of eukaryotic SSU rRNA gene sequences and the phylogenetic re-analysis of previously published environmental sequences using Bayesian methods, our results suggest that the number of novel higher-level taxa revealed by previously published EES was overestimated. Three main sources of errors are responsible for this situation: (1) the presence of undetected chimeric sequences; (2) the misplacement of several fast-evolving sequences; and (3) the incomplete sampling of described, but yet unsequenced eukaryotes. Additionally, EES give a biased view of the diversity present in a given biotope because of the difficult amplification of SSU rRNA genes in some taxonomic groups. CONCLUSIONS: Environmental DNA surveys undoubtedly contribute to reveal many novel eukaryotic lineages, but there is no clear evidence for a spectacular increase of the diversity at the kingdom level. After re-analysis of previously published data, we found only five candidate lineages of possible novel high-level eukaryotic taxa, two of which comprise several phylotypes that were found independently in different studies. To ascertain their taxonomic status, however, the organisms themselves have now to be identified.

Animals↗
PubMed2005

RNA interference: more than a research tool in the vertebrates' adaptive immunity.

In recent years, RNA silencing, usage of small double stranded RNAs of approximately 21 - 25 base pairs to regulate gene expression, has emerged as a powerful research tool to dissect the role of unknown host cell factors in this 'post-genomic' era. While the molecular mechanism of RNA silencing has not been precisely defined, the revelation that small RNA molecules are equipped with this regulatory function has transformed our thinking on the role of RNA in many facets of biology, illustrating the complexity and the dynamic interplay of cellular regulation. As plants and invertebrates lack the protein-based adaptive immunity that are found in jawed vertebrates, the ability of RNA silencing to shut down gene expression in a sequence-specific manner offers an explanation of how these organisms counteract pathogen invasions into host cells. It has been proposed that this type of RNA-mediated defence mechanism is an ancient form of immunity to offset the transgene-, transposon- and virus-mediated attack. However, whether 1) RNA silencing is a natural immune response in vertebrates to suppress pathogen invasion; or 2) vertebrate cells have evolved to counteract invasion in a 'RNA silencing' independent manner remains to be determined. A number of recent reports have provided tantalizing clues to support the view that RNA silencing functions as a physiological response to regulate viral infection in vertebrate cells. Amongst these, two manuscripts that are published in recent issues of Science and Immunity, respectively, have provided some of the first direct evidences that RNA silencing is an important component of antiviral defence in vertebrate cells. In addition to demonstrating RNA silencing to be critical to vertebrate innate immunity, these studies also highlight the potential of utilising virus-infection systems as models to refine our understanding on the molecular determinants of RNA silencing in vertebrate cells.

Animals↗
PubMed2006

Anti-viral RNA silencing: do we look like plants?

The anti-viral function of RNA silencing was first discovered in plants as a natural manifestation of the artificial 'co-suppression', which refers to the extinction of endogenous gene induced by homologous transgene. Because silencing components are conserved among most, if not all, eukaryotes, the question rapidly arose as to determine whether this process fulfils anti-viral functions in animals, such as insects and mammals. It appears that, whereas the anti-viral process seems to be similarly conserved from plants to insects, even in worms, RNA silencing does influence the replication of mammalian viruses but in a particular mode: micro(mi)RNAs, endogenous small RNAs naturally implicated in translational control, rather than virus-derived small interfering (si)RNAs like in other organisms, are involved. In fact, these recent studies even suggest that RNA silencing may be beneficial for viral replication. Accordingly, several large DNA mammalian viruses have been shown to encode their own miRNAs. Here, we summarize the seminal studies that have implicated RNA silencing in viral infection and compare the different eukaryotic responses.

Animals↗
PubMed2005

Virus-host interactions: new insights from the small RNA world.

RNA silencing has a known role in the antiviral responses of plants and insects. Recent evidence, including the finding that the Tat protein of human immunodeficiency virus (HIV) can suppress the host's RNA-silencing pathway and may thus counteract host antiviral RNAs, suggests that RNA-silencing pathways could also have key roles in mammalian virus-host interactions.

Animals↗
PubMed2005

Living on the edge.

A report on the Second EMBL/EMBO Symposium on Functional Genomics: 'Exploring the Edges of Omics', European Molecular Biology Laboratory (EMBL), Heidelberg, Germany, 16-19 October 2004.

Animals↗