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RBPMS inhibits bladder cancer metastasis by downregulating MYC pathway through alternative splicing of ANKRD10.

RNA-binding proteins (RBPs) are pivotal mediators of the alternative splicing (AS) machinery of pre-mRNA. Research has demonstrated that the AS process is significantly dysregulated and plays a crucial role in bladder cancer (BLCA). We conducted comprehensive screening and analysis of the TCGA-BLCA cohort, specifically focusing on genes with significant differences in expression levels between carcinoma and adjacent non-cancerous tissues. Among the 500 differentially expressed genes, 5 RNA-binding proteins were identified. Only the RNA-binding protein with multiple splicing (RBPMS) demonstrate

Highly Reactive Group I Introns Ubiquitous in Pathogenic Fungi.

Systemic fungal infections are a growing public health threat, and yet viable antifungal drug targets are limited as fungi share a similar proteome with humans. However, features of RNA metabolism and the noncoding transcriptomes in fungi are distinctive. For example, fungi harbor highly structured RNA elements that humans lack, such as self-splicing introns within key housekeeping genes in the mitochondria. However, the location and function of these mitochondrial riboregulatory elements has largely eluded characterization. Here we used an RNA-structure-based bioinformatics pipeline to identi

GPATCH11 variants cause mis-splicing and early-onset retinal dystrophy with neurological impairment.

Here we conduct a study involving 12 individuals with retinal dystrophy, neurological impairment, and skeletal abnormalities, with special focus on GPATCH11, a lesser-known G-patch domain-containing protein, regulator of RNA metabolism. To elucidate its role, we study fibroblasts from unaffected individuals and patients carrying the recurring c.328+1 G > T mutation, which specifically removes the main part of the G-patch domain while preserving the other domains. Additionally, we generate a mouse model replicating the patients' phenotypic defects, including retinal dystrophy and behavioral abn

Current developments in gene therapy for epidermolysis bullosa.

INTRODUCTION: The genodermatosis epidermolysis bullosa (EB) is a monogenetic disease, characterized by severe blister formation on the skin and mucous membranes upon minimal mechanical trauma. Causes for the disease are mutations in genes encoding proteins that are essential for skin integrity. In EB, one of these proteins is either functionally impaired or completely absent. Therefore, the development and improvement of DNA and RNA-based therapeutic approaches for this severe blistering skin disease is mandatory to achieve a treatment option for the patients. AREAS COVERED: Currently, there

Utilisation of a cryptic non-canonical donor splice site of the gene encoding PARAFIBROMIN is associated with familial isolated primary hyperparathyroidism.

More than 99% of all splice sites conform to consensus sequences that usually include the invariant dinucleotides gt and ag at the 5' and 3' ends of the introns, respectively. We report on the utilisation of a non-consensus (non-canonical) donor splice site within exon 1 of the HRPT2 gene in familial isolated primary hyperparathyroidism (FIHP). HRPT2 mutations are more frequently associated with the hyperparathyroidism-jaw tumour syndrome (HPT-JT). Patients with FIHP were identified to have a donor splice site mutation, IVS1+1 g-->a, and the consequences of this for RNA processing were investi

Cytoplasmic pool of U1 spliceosome protein SNRNP70 shapes the axonal transcriptome and regulates motor connectivity.

Regulation of pre-mRNA splicing and polyadenylation plays a profound role in neurons by diversifying the proteome and modulating gene expression in response to physiological cues. Although most of the pre-mRNA processing is thought to occur in the nucleus, numerous splicing regulators are also found in neurites. Here, we show that U1-70K/SNRNP70, a component of the major spliceosome, localizes in RNA-associated granules in zebrafish axons. We identify the extra-nuclear SNRNP70 as an important regulator of motor axonal growth, nerve-dependent acetylcholine receptor (AChR) clustering, and neurom…

The UNC13A cryptic exon associates with cognitive impairment in Alzheimer's disease.

BACKGROUND: TAR DNA-binding protein of 43 kDa (TDP-43) is often found in the brains of patients with Alzheimer's disease (AD), where it co-occurs with amyloid β plaques and tau neurofibrillary tangles, and associates with accelerated cognitive decline and brain atrophy. TDP-43's function of repressing the inclusion of cryptic exons (CEs) during RNA splicing is compromised in AD. A single-nucleotide polymorphism (SNP) located within the CE in the UNC13A gene [rs12973192 (C > G)] is associated with higher disease risk and reduced survival in amyotrophic lateral sclerosis (ALS) and frontotemporal…

Genome editing of patient-derived iPSCs identifies a deep intronic variant causing aberrant splicing in hemophilia A.

The importance of genetic diagnosis for patients with hemophilia has been recently demonstrated. However, the pathological variant cannot be identified in some patients. Here, we aimed to identify the pathogenic intronic variant causing hemophilia A using induced pluripotent stem cells (iPSCs) from patients and genome editing. We analyzed siblings with moderate hemophilia A and without abnormalities in the F8 exon. Next-generation sequencing of the entire F8 revealed 23 common intron variants. Variant effect predictor software indicated that the deep intronic variant at c.5220-8563A>G (intron

Minute Virus of Canines NP1 Protein Interacts with the Cellular Factor CPSF6 To Regulate Viral Alternative RNA Processing.

The NP1 protein of minute virus of canines (MVC) governs production of the viral capsid proteins via its role in pre-mRNA processing. NP1 suppresses polyadenylation and cleavage at its internal site, termed the proximal polyadenylation (pA)p site, to allow accumulation of RNAs that extend into the capsid gene, and it enhances splicing of the upstream adjacent third intron, which is necessary to properly enter the capsid protein open reading frame. We find the (pA)p region to be complex. It contains redundant classical cis-acting signals necessary for the cleavage and polyadenylation reaction a

Transcript-Targeted Therapy Based on RNA Interference and Antisense Oligonucleotides: Current Applications and Novel Molecular Targets.

The development of novel target therapies based on the use of RNA interference (RNAi) and antisense oligonucleotides (ASOs) is growing in an exponential way, challenging the chance for the treatment of the genetic diseases and cancer by hitting selectively targeted RNA in a sequence-dependent manner. Multiple opportunities are taking shape, able to remove defective protein by silencing RNA (e.g., Inclisiran targets mRNA of protein PCSK9, permitting a longer half-life of LDL receptors in heterozygous familial hypercholesteremia), by arresting mRNA translation (i.e., Fomivirsen that binds to UL1

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… RNA splicing process analysis for identifying antisense oligonucleotide inhibitors with padlock probe-based isothermal amplification. Chem. Sci. 2017;8:5692–5698. doi: 10.1039/C7SC01336A. 11. Siva K., Covello G., Denti M.A. …

Comprehensive transcriptomic analysis shows disturbed calcium homeostasis and deregulation of T lymphocyte apoptosis in inclusion body myositis.

OBJECTIVE: Inclusion body myositis (IBM) has an unclear molecular etiology exhibiting both characteristic inflammatory T-cell activity and rimmed-vacuolar degeneration of muscle fibers. Using in-depth gene expression and splicing studies, we aimed at understanding the different components of the molecular pathomechanisms in IBM. METHODS: We performed RNA-seq on RNA extracted from skeletal muscle biopsies of clinically and histopathologically defined IBM (n = 24), tibial muscular dystrophy (n = 6), and histopathologically normal group (n = 9). In a comprehensive transcriptomics analysis, we an

Identification of Genomewide Alternative Splicing Events in Sequential, Isogenic Clinical Isolates of Candida albicans Reveals a Novel Mechanism of Drug Resistance and Tolerance to Cellular Stresses.

Alternative splicing (AS)-a process by which a single gene gives rise to different protein isoforms in eukaryotes-has been implicated in man … ensitive and -resistant isolates of C. albicans, here, we show how C. albicans uses modulations in mRNA splicing to overcome antifungal drug stress.

Enhanced antisense oligonucleotide delivery reveals that transcript turnover impacts apparent splicing rescue in myotonic dystrophy.

Steric-blocking antisense oligonucleotides rescue myotonic dystrophy type 1 phenotypes in preclinical models and are under evaluation in clinical trials. However, the rationale for biomarker selection remains a topic of debate. Here, we show that a cyclic cell-penetrating peptide that escapes endosomes enhances muscle delivery of a phosphorodiamidate morpholino oligonucleotide designed to block pathogenic CUG repeat expansions in HSALR mice. A single systemic administration rescued mis-splicing and eliminated myotonia 1 week post-injection, with partial splicing rescue evident after 24 h. Inte

SRSF1 and SRSF2 synergistically regulate Bim expression to mediate glucocorticoid-induced apoptosis in osteoblasts.

Further study of glucocorticoid (GC) -induced osteoblast (OB) apoptosis and its regulatory mechanism is an important direction to explore the therapeutic strategy of steroid-induced osteonecrosis of the femoral head (SONFH) and steroid-induced osteoporosis. The aim of this study is to elucidate the role and mechanism of splicing factors serine/arginine-rich splicing factor 1 (SRSF1) and SRSF2 in GC-induced OB apoptosis. Transcriptome sequencing and bioinformatics prediction showed that the expression of SRSF1 and SRSF2 was significantly down-regulated in GC-treated OB and was related to GC-ind

Transcriptomic Alterations in Spliceosome Components in Advanced Heart Failure: Status of Cardiac-Specific Alternative Splicing Factors.

Heart failure (HF) is associated with global changes in gene expression. Alternative mRNA splicing (AS) is a key regulatory mechanism underlying these changes. However, the whole status of molecules involved in the splicing process in human HF is unknown. Therefore, we analysed the spliceosome transcriptome in cardiac tissue (n = 36) from control subjects and HF patients (with ischaemic (ICM) and dilated (DCM) cardiomyopathies) using RNA-seq. We found greater deregulation of spliceosome machinery in ICM. Specifically, we showed widespread upregulation of the E and C complex components, highlig…

Antisense oligonucleotide therapeutics in clinical trials for the treatment of inherited retinal diseases.

INTRODUCTION: Antisense oligonucleotides (ASOs) represent a class of drugs which can be rationally designed to complement the coding or non-coding regions of target RNA transcripts. They could modulate pre-messenger RNA splicing, induce mRNA knockdown, or block translation of disease-causing genes, thereby slowing disease progression. The pharmacokinetics of intravitreal delivery may enable ASOs to be effective in the treatment of inherited retinal diseases. AREAS COVERED: We review the current status of clinical trials of ASO therapies for inherited retinal diseases, which have demonstrated …

The intellectual disability gene PQBP1 rescues Alzheimer's disease pathology.

Early-phase pathologies of Alzheimer's disease (AD) are attracting much attention after clinical trials of drugs designed to remove beta-amy … ed in cortical neurons of human AD patients and mouse AD models, and the AAV-PQBP1 vector recovered RNA splicing, the synapse phenotype, and the cognitive decline in the two mouse models. Finally, the kinases responsible for the phosphorylation of SRRM2 at Ser1068 were identified as ERK1/2 (MAPK3/1). These results collectively reveal a new aspect of AD patholo …

Spliceosome Mutations Induce R Loop-Associated Sensitivity to ATR Inhibition in Myelodysplastic Syndromes.

Heterozygous somatic mutations in spliceosome genes (U2AF1, SF3B1, ZRSR2, or SRSF2) occur in >50% of patients with myelodysplastic syndrome (MDS). These mutations occur early in disease development, suggesting that they contribute to MDS pathogenesis and may represent a unique genetic vulnerability for targeted therapy. Here, we show that RNA splicing perturbation by expression of the U2AF1(S34F) mutant causes accumulation of R loops, a transcription intermediate containing RNA:DNA hybrids and displaced single-stranded DNA, and elicits an ATR response. ATR inhibitors (ATRi) induced DNA damage …

Characterizing Expression and Regulation of Gamma-Herpesviral Circular RNAs.

Multiple herpesviruses have been recently found to encode viral circular RNAs. Like cellular circular RNAs, these RNAs lack poly-A tails and their 5' and 3' ends have been joined, which confers protection from RNA exonucleases. We examined the expression patterns of circular RNAs from Kaposi's sarcoma herpesvirus (KSHV) in various environments. We performed deep sequencing of circRNA-enriched total RNA from a KSHV-positive patient lymph node for comparison with previous circRNA-Seq results. We found that circvIRF4 is highly expressed in the KSHV-positive patient sample relative to both B cell

MBNL deficiency in motor neurons disrupts neuromuscular junction maintenance and gait coordination.

Muscleblind-like proteins (MBNLs) are a family of RNA-binding proteins that play essential roles in the regulation of RNA metabolism. Beyond their canonical role in RNA regulation, MBNL proteins have emerged as key players in the pathogenesis of myotonic dystrophy type 1. In myotonic dystrophy type 1, sequestration of MBNL proteins by expansion of the CUG repeat RNA leads to functional depletion of MBNL, resulting in deregulated alternative splicing and aberrant RNA processing, which underlie the clinical features of the disease. Although attention on MBNL proteins has focused on their functio