RNA Biol [JOURNAL]
Sun
200 papers
RNA polymerase II phosphorylation dynamics: from molecular mechanisms to human disease.
González-Jiménez A, Medina I, Alfonso MJ … +2 more , Vázquez de Aldana CR, Calvo O
RNA Biol · 2026 Dec · PMID 42370638 · Publisher ↗
Accurate RNA polymerase II (RNAPII)-dependent gene expression requires dynamic phosphorylation of the carboxy-terminal domain (CTD) of its largest subunit, Rpb1, whose heptapeptide repeats form a regulatory platform know...
Accurate RNA polymerase II (RNAPII)-dependent gene expression requires dynamic phosphorylation of the carboxy-terminal domain (CTD) of its largest subunit, Rpb1, whose heptapeptide repeats form a regulatory platform known as the CTD code. Transcription-associated cyclin-dependent kinases (tCDKs) and CTD phosphatases coordinate the phosphorylation - dephosphorylation cycle of RNAPII throughout transcription, coupling RNA synthesis to co-transcriptional processing and chromatin regulation. By controlling stage-specific modification of the CTD, these enzymes integrate RNAPII activity into broader regulatory networks. Disruption of the delicate kinase - phosphatase balance impairs transcriptional fidelity, RNA maturation, and genome stability, either directly through altered CTD phosphorylation or indirectly through associated pathways. Such alterations are increasingly associated with developmental disorders, neurodegeneration, and cancer. Here, we synthesize current knowledge of RNAPII phosphorylation dynamics, highlighting key mechanistic principles, links to human disease, and emerging therapeutic strategies targeting this central phosphorylation-dependent regulatory system.
Impact of interspecies colostrum and milk replacement on circulating sncRNA dynamics of neonatal goat kids.
Dekker RJ, van den Esker MH, Ravesloot L … +5 more , de Leeuw WC, van Olst M, Jonker MJ, Breit TM, Koets AP
RNA Biol · 2026 Dec · PMID 42359946 · Full text
Replacing maternal colostrum and milk with those from other species is common practice in neonatal ruminant management, but the effects on small non-coding RNA (sncRNA) transmission remain poorly understood. This study i...
Replacing maternal colostrum and milk with those from other species is common practice in neonatal ruminant management, but the effects on small non-coding RNA (sncRNA) transmission remain poorly understood. This study investigated whether colostrum and milk replacement alters circulating sncRNA profiles in neonatal goats using a twin-pair model. Six vaccinated goat dams ( ssp. ) and their twelve kids were included. One goat twin kid received maternal colostrum and milk, while the other was fed a replacement diet with bovine colostrum and milk replacer. Small RNA sequencing was performed on serum samples from kids, as well as on goat colostrum and milk and on bovine replacers. All colostrum and milk samples contained diverse sncRNAs, including miRNAs, and tRNA- and rRNA-derived fragments. Processing and storage influenced sncRNA abundance and stability. In neonatal serum, sncRNA profiles changed during development and indicated two response waves: after colostrum replacement and after three weeks of continued milk replacement. These changes involved differential abundance of miRNAs and rRNA-derived fragments, including molecules linked to immune regulation, metabolism, and developmental pathways. Although sequence similarity between bovine and caprine sncRNAs limited direct inference of dietary transfer, the observed differences suggest that milk origin and composition may influence circulating sncRNA profiles. Several milk-associated miRNAs were consistently detected in serum, suggesting potential maternal transfer. Overall, these findings indicate that interspecies milk replacement may modify neonatal circulating sncRNAs, highlighting a potential role for milk-derived sncRNAs in shaping early-life immune and developmental programming.
The role of RNA modifications in cancer translational control.
Joy M, Cleynen A, Shirokikh NE
RNA Biol · 2026 Dec · PMID 42343618 · Publisher ↗
RNA modifications have emerged as central regulators of cancer translational control. Unlike transcriptional reprogramming, which unfolds over hours, modification-dependent translational rewiring enables rapid proteomic...
RNA modifications have emerged as central regulators of cancer translational control. Unlike transcriptional reprogramming, which unfolds over hours, modification-dependent translational rewiring enables rapid proteomic adaptation to the nutrient-deprived, hypoxic, and immunologically hostile tumour microenvironment. Yet most existing reviews organize epitranscriptomic mechanisms by modification type or cancer hallmark, obscuring the mechanistic logic by which chemical marks collectively reshape the translational apparatus. This review adopts a translation-centric framework, examining how the most abundant modifications on mRNAs, tRNAs, and rRNAs regulate each stage of protein synthesis in malignant cells. We survey the epitranscriptomic toolkit, including modification chemistries, enzymatic writers, readers, and erasers, and detection technologies including nanopore direct RNA sequencing. We then trace how modifications control initiation (m6A-driven mRNA circularization, cap-independent translation eIF3 and eIF4G2, rRNA 2'-O-methylation-directed cap-to-IRES switching), elongation (m6A-induced ribosome stalling coupled to mRNA decay, tRNA mcm5s2U-mediated codon-biased translation, YTHDF1-dependent elongation factor recruitment), and termination (pseudouridine-mediated stop codon readthrough, NMD evasion). Crucially, we show that mRNA, tRNA, and rRNA modifications do not act in isolation but form integrated networks. For example, mRNA m6A and tRNA mcm5s2U operate on opposing arms of the same regulatory axis, with direct implications for therapeutic design. We assess the expanding drug pipeline, from the METTL3 inhibitor STC-15 now in Phase 1b/2 trials and METTL3-targeting PROTACs to FTO and ADAR1 inhibitors, and argue that biology-informed combination strategies targeting multiple modification axes will be essential for durable clinical responses.
Discovery of a mutation-containing circRNA in polyglutamine disease through systematic analysis of RNAs with CAG repeats.
Pawlik W, Woźna-Wysocka M, Jazurek-Ciesiołka M … +11 more , Dulski J, Witkoś TM, Ciołak A, Kozłowska E, Kościańska E, Bartelt LC, Philippe J, Sławek J, Świtoński PM, La Spada AR, Fiszer A
RNA Biol · 2026 Dec · PMID 42340810 · Full text
CAG repeat tracts occur in both non-coding and translated RNAs, have tended to lengthen throughout evolution, and are thought to enhance neuronal function. We identified over 600 human RNAs (including mRNAs, lncRNAs, and...
CAG repeat tracts occur in both non-coding and translated RNAs, have tended to lengthen throughout evolution, and are thought to enhance neuronal function. We identified over 600 human RNAs (including mRNAs, lncRNAs, and circRNAs) with at least 10 CAG repeats, originating from 58 genomic , which vary, e.g. in the rate of CAG length polymorphism. Several circRNAs originate from the locus, where CAG expansion causes spinocerebellar ataxia type 7 (SCA7). For selected (circ1), we demonstrated its cytoplasmic localization, as well as its presence in 40S, monosome and polysome fractions. We showed that circ1 is expressed in human fibroblasts, blood and cerebellum, and, importantly, we identified a mutation-containing circRNA with potential implications in SCA7.
FDA-approved antisense oligonucleotide therapies for duchenne muscular dystrophy: current status and future outlook.
Moriyama H, Moriyama S, Yokota T
RNA Biol · 2026 Dec · PMID 42324661 · Full text
Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive disorder caused by dystrophin deficiency. Antisense oligonucleotide (ASO)-mediated exon skipping has emerged as a cornerstone of DMD therapy to restore dyst...
Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive disorder caused by dystrophin deficiency. Antisense oligonucleotide (ASO)-mediated exon skipping has emerged as a cornerstone of DMD therapy to restore dystrophin expression. This review provides a comprehensive overview of the four FDA-approved ASO therapies - eteplirsen, golodirsen, viltolarsen, and casimersen - tracing their journey from pivotal clinical trials to post-marketing updates. While the development and clinical evaluation of these agents have established a pioneering framework for rare genetic diseases, they have also highlighted critical challenges. These include complexities in clinical trial design, discrepancies between preclinical efficacy and clinical outcomes, real-world burdens, and limited patient eligibility. Furthermore, the FDA's accelerated approval of these therapies based on limited clinical data remains a subject of ongoing debate. Confirmatory trials to verify clinical efficacy and long-term follow-up studies are actively underway. Concurrently, intensive research is focused on developing next-generation ASOs to achieve enhanced therapeutic efficacy and definitive clinical outcomes. Elucidating the trajectory of research and development in this field offers profound insights for shaping future therapeutic strategies in rare diseases.
The RNA binding protein ZFP36L2 displays tissue-selective mRNA targeting in mice.
Stephenson GS, Fleifel D, Cook JG … +2 more , Laederach A, Ramos SBV
RNA Biol · 2026 Dec · PMID 42319349 · Full text
ZFP36L2 (zinc finger protein 36 like 2, C3H type-ZFP) is an RNA-binding protein targeting transcripts rich in adenine-uridine elements (AREs). Previous transcriptomic analysis suggested that ZFP36L2 displays a distinct t...
ZFP36L2 (zinc finger protein 36 like 2, C3H type-ZFP) is an RNA-binding protein targeting transcripts rich in adenine-uridine elements (AREs). Previous transcriptomic analysis suggested that ZFP36L2 displays a distinct transcript preference or 'specific activity'. However, this analysis was restricted to a few tissues. Here, using experimental data in multiple tissues we detected a remarkable transcript selectivity depending on the tissue. Given that ZFP36L2 accelerates the degradation of specific ARE-transcripts upon binding, we obtained differential expression transcriptomic data on a Zfp36l2 knock-out mouse model to delve into the mechanisms governing this tissue-specific targeting. Transcriptomic analyzes of up-regulated ARE-transcripts in six tissues, lung, liver, bone marrow, spleen, kidney, and ovary of the Zfp36l2-deficient mouse confirmed that there is high tissue preference in ZFP36L2 targets. We observed only one common up-regulated gene, Apol11b, among these six different tissues. However, we do observe common trends, specifically an enrichment in protein coding genes in the up-regulated genes, consistent with these RBP primarily targeting genes on their 3' UTRs. Interestingly, we observed a significant increase in the proportion of IgV (immunoglobulin) genes being up-regulated. We further performed eCLIP (Enhanced Cross-Linking&ImmunoPreciptation) on a mouse cell line to explore potential binding sites of ZFP36L2. AU-Rich Element score (AREscore) analysis revealed enrichment in both up-regulated genes and eCLIP peaks, although some differences were observed in flanking residue composition. Our findings provide new insights into the intricate regulatory network orchestrated by ZFP36L2, opening avenues for exploring its potential roles in different tissues.
Biological consequences of Z-nucleic acid sensing by ZBP1 and ADAR1.
Lu F, Tang L, Kim C … +3 more , Lai D, Tou J, Jiao H
RNA Biol · 2026 Dec · PMID 42311118 · Full text
Since their discovery, Z-nucleic acids (Z-NAs), which adopt a left-handed double helical conformation, have puzzled researchers regarding their physiological functions. These unusual nucleic acids are recognized by prote...
Since their discovery, Z-nucleic acids (Z-NAs), which adopt a left-handed double helical conformation, have puzzled researchers regarding their physiological functions. These unusual nucleic acids are recognized by proteins containing Zα domains, particularly Z-DNA binding protein 1 (ZBP1) and adenosine deaminase acting on RNA 1 (ADAR1). Utilizing mouse genetics with knockout models and site-specific Zα domain mutations, scientists have revealed that Z-NAs serve as critical regulators of programmed cell death, inflammation, antiviral immunity, and anti-tumour responses. This review systematically examines mechanistic insights from - and -mutant models, illuminating how Z-NAs play a dual role as essential triggers of host defence and as potential drivers of autoinflammatory diseases.
Crosstalk between circRNAs and the classic signaling pathways in IBD.
Jie M, Liao Q, Liu C
RNA Biol · 2026 Dec · PMID 42290604 · Full text
Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), is a chronic inflammatory disorder of the gastrointestinal tract with a complex aetiology involving genetic, environmenta...
Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), is a chronic inflammatory disorder of the gastrointestinal tract with a complex aetiology involving genetic, environmental (such as diet/lifestyle), and microbiota factors. The exact pathogenesis of IBD remains unclear, and current therapies show limited effectiveness. Circular RNAs (circRNAs) are a novel class of noncoding RNAs that have been implicated in the regulation of various biological processes. Many circRNAs show specific expression profiles in IBD patients and play important roles in IBD pathogenesis through different signalling pathways, such as the Janus kinase/signal transducer and activator of transcription (JAK/STAT) and nuclear factor-κB (NF-κB) pathways. Although research on circRNAs in IBD is still in its early stages, many circRNAs have emerged as potential diagnostic, prognostic biomarkers, and therapeutic targets for IBD. Here, we summarize the molecular functions and underlying mechanisms of circRNAs in IBD and discuss current challenges and future perspectives for clinical applications.
The RNA exosome: mechanisms of RNA surveillance, regulation, and disease.
Upadhyai P, Quadri N, Chandran D
RNA Biol · 2026 Dec · PMID 42275096 · Full text
The RNA exosome is a conserved multi-subunit ribonuclease complex with pivotal roles in RNA biogenesis, surveillance, and processing. It comprises a nine-subunit scaffold that associates with distinct ribonucleases in a...
The RNA exosome is a conserved multi-subunit ribonuclease complex with pivotal roles in RNA biogenesis, surveillance, and processing. It comprises a nine-subunit scaffold that associates with distinct ribonucleases in a cell compartment-specific manner, contributing to the processing and turnover of a broad spectrum of nuclear and cytoplasmic transcripts, including pervasively transcribed and short-lived RNAs, precursors, and abortive and aberrant transcripts. In this review, we examine how the RNA exosome engages a wide spectrum of RNAs via differential adaptor usage and intrinsic substrate features, such as transcript length and 3' end structure. This also modulates the entry routes of the recruited transcripts. We highlight conserved principles and major differences between yeast and metazoans. We assimilate emerging evidence that suggests that the RNA exosome localization and activity are dynamically regulated in response to cellular context and external stimuli. Finally, drawing on findings from studies in , zebrafish, and mice, we discuss how perturbations in RNA surveillance can result in abnormalities in organismal development and homoeostasis. Together, these studies not only enhance our knowledge of the broader relevance of RNA quality control and metabolism but also provide mechanistic insights into pathomechanisms, particularly the tissue-specific vulnerabilities noted in RNA exosome-linked diseases.
FTO-mediated mA demethylation of BCL6 promotes gastric cancer progression by suppressing ferroptosis.
Wang Y, Fan F, Zhan Z … +2 more , Yu C, Chen S
RNA Biol · 2026 Dec · PMID 42262009 · Full text
B-cell lymphoma 6 (BCL6) functions in various cancers, but its role and regulation in gastric cancer (GC) remain unclear. N-methyladenosine (mA) modification is critical for tumorigenesis, and the demethylase FTO (highly...
B-cell lymphoma 6 (BCL6) functions in various cancers, but its role and regulation in gastric cancer (GC) remain unclear. N-methyladenosine (mA) modification is critical for tumorigenesis, and the demethylase FTO (highly expressed in GC) may regulate target gene stability via mA. This study explored FTO's regulation of BCL6 mA modification and its impact on GC progression through ferroptosis. qPCR assessed BCL6 expression in GC cells. BCL6 overexpression models were used to evaluate cell viability, apoptosis, and ferroptosis (via ROS, Fe, MDA, LDH, and ferroptosis-related proteins). RIP-PCR, MeRIP-qPCR, and mRNA stability assays examined FTO-BCL6 mRNA interaction and mA effects. YTHDF2 knockdown validated its role, and co-silencing FTO/BCL6 clarified the axis's function. BCL6 was downregulated in GC cells. Its overexpression inhibited cell viability, promoted apoptosis, and induced ferroptosis. FTO bound BCL6 mRNA, removed mA, and reduced its stability. YTHDF2 mediated FTO's negative regulation of BCL6. FTO knockdown enhanced ferroptosis and impaired GC cell function, partially reversed by BCL6 silencing. FTO suppresses BCL6 via mA demethylation, inhibiting ferroptosis to promote GC progression. The FTO/BCL6 axis is a potential therapeutic target for GC.
Enhancer RNAs: similarities with both lncRNAs and mRNAs reveal novel functions.
Vlasov PA, Manley JL
RNA Biol · 2026 Dec · PMID 42261755 · Full text
Cells produce numerous types of RNAs. Among these, transcripts produced by RNA polymerase II include protein-coding mRNAs as well as a variety of long noncoding RNAs. In this latter group, enhancer (e) RNAs constitute a...
Cells produce numerous types of RNAs. Among these, transcripts produced by RNA polymerase II include protein-coding mRNAs as well as a variety of long noncoding RNAs. In this latter group, enhancer (e) RNAs constitute a class of RNAs transcribed from enhancer sites. Although eRNAs are typically unstable and degraded rapidly, multiple roles related to enhancer function have been suggested. But eRNAs also share similarities with mRNAs, such as in a limited number the presence of translated open reading frames. Indeed, other "noncoding" RNAs have also been found to contain coding sequences, and together these transcripts blur the line between coding and noncoding. Here, we review current models of eRNA function, the discoveries that led to them, and additional functions, specifically the potential for translation. We also review the characteristics of proteins encoded by such "noncoding" transcripts, and their possible implications regarding the function and evolution of both eRNAs and mRNAs.
Identification of proteins exhibiting RNA chaperone activity through gradient profiling in the Lyme disease spirochete, .
Van Gundy T, Schneider C, Ebmeier CC … +9 more , Chambers GZ, Cramer NA, Chambers KM, Drecktrah D, Hyde JA, Skare JT, Marconi RT, Samuels DS, Lybecker MC
RNA Biol · 2026 Dec · PMID 42233734 · Full text
RNA-binding proteins (RBPs) play key roles in regulating gene expression across all domains of life. However, relatively few RBPs have been discovered and characterized in () , the causative agent of Lyme disease. We ut...
RNA-binding proteins (RBPs) play key roles in regulating gene expression across all domains of life. However, relatively few RBPs have been discovered and characterized in () , the causative agent of Lyme disease. We utilized gradient profiling to identify putative RBPs that co-sediment with small RNAs (sRNAs) and nascent mRNAs. The previously hypothetical proteins BB0749, BB0713 and BB0796, as well as the chemotaxis-related protein CheY2 and the flagella-associated protein FlgV demonstrated RNA unwinding (structural remodeling), RNA annealing, and strand displacement activity. Moreover, co-IP assays demonstrated BB0749 binds RNA in .
The RNA-binding activity of the Brat protein is necessary for viability and mRNA regulation.
Connacher RP, Hu Y, Roden R … +5 more , Toledo J, DesMarais A, O'Connor M, Lipshitz HD, Goldstrohm AC
RNA Biol · 2026 Dec · PMID 42206510 · Full text
Brain tumor (Brat) is a TRIM-NHL protein required for embryogenesis and neural stem cell differentiation. Although structural and biochemical studies established that the Brat NHL domain specifically binds RNA, the in v...
Brain tumor (Brat) is a TRIM-NHL protein required for embryogenesis and neural stem cell differentiation. Although structural and biochemical studies established that the Brat NHL domain specifically binds RNA, the in vivo requirement for this activity has not been directly tested. Here, we used structure-guided mutagenesis and genome engineering to determine whether RNA recognition is essential for Brat function during development. The direct interaction between Brat's NHL domain and RNA containing Brat Binding Sites (BBS) can be abolished by alanine substitution of three separate residues on the NHL surface. We introduced these point mutations into the endogenous locus by CRISPR-mediated Scarless Gene Editing to generate three independent RNA-binding defective mutant (RBDmt) alleles. Complementation tests demonstrated that each allele behaves as a strong loss-of-function mutation: homozygotes and hemizygotes are inviable, and RBDmt alleles fail to complement classical null and hypomorphic alleles. Lethal phase analysis revealed death predominantly during late larval and pupal stages, consistent with known alleles. Consistent with the namesake phenotype, RBDmt larval brains exhibited widespread expression of neuroblast markers and a marked reduction of neuronal differentiation. In embryos, these alleles failed to complement female sterile alleles and recapitulated characteristic abdominal segmentation defects. Finally, RT-qPCR showed increased expression of endogenous Brat target mRNAs in mutant larvae, consistent with loss of Brat-mediated repression. Together, these results demonstrate that direct RNA binding is an essential molecular activity of Brat and that post-transcriptional regulation of Brat target mRNAs underlies its critical roles across development.
The role of miRNA in modulating oxidative stress in preeclampsia: current knowledge.
Lin C, Xu Q, Yan J … +3 more , Cao B, Song Y, Tang C
RNA Biol · 2026 Dec · PMID 42200378 · Full text
Preeclampsia (PE), a gestational disorder diagnosed with hypertension and proteinuria, is recognized as a significant cause of both maternal and perinatal morbidity and mortality around the world. Oxidative stress (OS) i...
Preeclampsia (PE), a gestational disorder diagnosed with hypertension and proteinuria, is recognized as a significant cause of both maternal and perinatal morbidity and mortality around the world. Oxidative stress (OS) is found to act as a major positive role in PE progression, which is regulated by the function derived from multiple microRNAs (miRNAs), a group of cellular small endogenous RNAs that modulate gene expression at post-transcriptional level. This review summarizes the role of different miRNAs in the PE development, focusing on their involvement in OS regulation. In addition, the paper also discusses the current knowledge of the molecular mechanisms regarding PE and highlights the possibly therapeutic implications of targeting miRNAs in the management of this condition.
Presence and function of small RNAs during plant reproduction.
Yang AS, Tang AM, Gehring M
RNA Biol · 2026 Dec · PMID 42186994 · Full text
Plants possess an expansive suite of epigenetic control mechanisms to keep their large, repetitive, and unruly genomes in check. Small non-coding RNAs constitute one such mechanism by directing transcriptional and post-t...
Plants possess an expansive suite of epigenetic control mechanisms to keep their large, repetitive, and unruly genomes in check. Small non-coding RNAs constitute one such mechanism by directing transcriptional and post-transcriptional gene silencing. Small RNAs come in several forms that are produced by distinct pathways, including microRNAs and small interfering RNAs, such as tasiRNAs, phasiRNAs, and RNA Polymerase IV (Pol IV)-dependent small RNAs. Compared to other classes of small RNAs, Pol IV-dependent small RNAs and phasiRNAs appear to have the greatest phenotypic impact during the reproductive phase of the life cycle, from meiosis through seed development. Here, we focus on the function of 21-24 nucleotide small RNAs during reproduction, with a primary focus on Pol IV-dependent small RNAs. We critically assess the evidence surrounding their mode of action, specifically whether they act in or in , cell autonomously or non-autonomously, and within or between generations.
miR-34 regulates cuticle pigmentation by targeting and in .
Liu Z, Yang D, Luo X … +1 more , Huang Y
RNA Biol · 2026 Dec · PMID 42186345 · Full text
Pigmentation is an orchestrated process involved in cuticle melanization and sclerotization in insects, and plays a critical role in maintaining the structural integrity and functional completeness of the insect cuticle....
Pigmentation is an orchestrated process involved in cuticle melanization and sclerotization in insects, and plays a critical role in maintaining the structural integrity and functional completeness of the insect cuticle. Although the cascade reactions underlying pigmentation have been extensively studied, our understanding of the involvement of miRNA in this process remains limited. Here, we investigate the role of conserved microRNA-34 (miR-34) in regulating cuticular colouration in the silkworm, . Overexpression of miR-34 led to pronounced melanization in the larval abdomen. Mechanistically, LC/MS analysis revealed that miR-34 overexpression alters the epidermal amino acid composition, with a particularly notable increase in tyrosine and dopamine content. Enzyme activity assays confirmed the activation of phenoloxidase (PO). Through experimental validation, we identified two key target genes of miR-34, including (a critical gene in melanin synthesis) and (a regulator of the serine protease cascade). This study uncovers a previously unreported miRNA mediated regulatory mechanism in insects and systematically elucidates how miR-34 coordinately modulates pigmentation through distinct molecular pathways, providing novel theoretical insights into this field.
Identification of proteins interacting with the N-terminal half of endoribonuclease RNase E in .
Göpel Y, Durica-Mitic S, Boyko S … +4 more , Dudys P, Amman F, Schnetz K, Görke B
RNA Biol · 2026 Dec · PMID 42167936 · Full text
In endoribonuclease RNase E (Rne) plays a central role in RNA processing and decay. Rne consists of an N-terminal catalytic domain (NTD) and a C-terminal scaffolding domain, separated by a membrane targeting sequence (M...
In endoribonuclease RNase E (Rne) plays a central role in RNA processing and decay. Rne consists of an N-terminal catalytic domain (NTD) and a C-terminal scaffolding domain, separated by a membrane targeting sequence (MTS). While the scaffolding domain represents a hub for interaction, only few proteins are known to bind the Rne-NTD. One example is protein RapZ, which forms a transient complex with the Rne-NTD to target a small RNA to decay. Here, we screened a genomic bacterial two-hybrid library for proteins binding to the Rne N-terminal half including the MTS. We identified fragments of 43 proteins, of which 15 were validated to bind Rne as full-length proteins. We distinguished three groups: Group I likely uses a membrane domain to bind a segment in Rne that contains the MTS. Group II proteins are cytoplasmic and bind the Rne-NTD. Group III proteins bind the Rne-NTD and additionally the MTS region, indicating two distinct interaction surfaces. RNA-seq revealed that overproduction of three group II proteins including YegJ generates similar effects on the transcriptome. Genes carrying Rne cleavage sites were enriched among downregulated genes but depleted from upregulated genes, suggesting altered RNA decay. Interestingly, strong overexpression of destabilizes rRNA and arrests growth. Apparently, YegJ damages the membrane, granting periplasmic RNase I and presumably also Rne access to cytoplasmic rRNA. We present a catalogue of proteins likely binding the Rne N-terminal half, which may provide a valuable resource for further investigation of these interactions and their roles.
Chromatin remodelling: a driving force in reverse mechanotransduction.
Buisson J, Colin F, Labernadie A … +2 more , Rabineau M, Vautier D
RNA Biol · 2026 Dec · PMID 42163430 · Full text
Chromatin serves as the dynamic carrier of genetic and epigenetic information in eukaryotic cells, playing a pivotal role in maintaining nuclear shape, mechanical stability, and cellular function. Aberrant nuclear morpho...
Chromatin serves as the dynamic carrier of genetic and epigenetic information in eukaryotic cells, playing a pivotal role in maintaining nuclear shape, mechanical stability, and cellular function. Aberrant nuclear morphology, often observed in mechanically stressed environments or diseases such as progeria and muscular dystrophy, correlates with nuclear dysfunction, DNA damage, and disrupted mechanotransduction. Chromatin exists in two main configurations - compacted heterochromatin and decompacted euchromatin - each regulating gene expression and cellular behaviour through epigenetic modifications. Histone acetyltransferases and deacetylases modulate chromatin compaction, while histone methylation introduces further regulatory complexity. Chromatin's viscoelastic properties enable it to store and restore mechanical energy, acting as a mechanosensitive component within the nucleus. External forces propagate from the extracellular matrix through focal adhesions, the cytoskeleton, and the nuclear lamina to chromatin, forming a direct mechanotransduction pathway. However, the reverse pathway - how internal nuclear forces generated during chromatin remodelling influence the nuclear membrane, cytoskeleton, and cell adhesion - remains poorly understood. This review explores the role of chromatin as a tensegrity element, capable of generating mechanical forces through condensate formation. It examines evidence supporting chromatin decompaction as a regulator of reverse mechanotransduction and identifies potential mechanical partners involved in this process. Understanding these mechanisms may elucidate how chromatin dynamics contribute to cellular fate decisions and disease pathogenesis.
Nusinersen: the antisense oligonucleotide at the forefront of spinal muscular atrophy treatment.
Singh NN, Ottesen EW, Singh RN
RNA Biol · 2026 Dec · PMID 42149739 · Full text
Spinal muscular atrophy (SMA) is the first human disease to be treated with an antisense oligonucleotide (ASO) that restores the full coding sequence of a mRNA through splicing modulation. The therapeutic ASO nusinersen...
Spinal muscular atrophy (SMA) is the first human disease to be treated with an antisense oligonucleotide (ASO) that restores the full coding sequence of a mRNA through splicing modulation. The therapeutic ASO nusinersen (marketed as Spinraza) targets intronic splicing silencer N1 (ISS-N1) located downstream of the predominantly skipped exon 7 of () gene. The full-length transcript of codes for SMN, an essential housekeeping protein with a prominent role in RNA metabolism. The success of nusinersen could be attributed at least in part to the accessibility of ISS-N1 that was found to have a strong inhibitory effect on splicing of exon 7. Nusinersen has saved thousands of lives affected by SMA. However, limitations of an ASO-based therapy continue to emerge. Here we describe lessons learned from ASO-mediated splicing corrections in general and nusinersen in particular. Specific focus of this review is to discuss how information gleaned from the off-target effects of nusinersen could be utilized to develop next generation of ASO-based therapies with improved efficacies.
Comprehensive profiling and molecular characterization of alternative splicing regulation in synaptic remodelling associated with neuropathic pain induced by chronic constrictive injury in a rat model.
Zhou J, Jia Y, Song W … +2 more , Zhang Y, Xia Z
RNA Biol · 2026 Dec · PMID 42137963 · Full text
Neuropathic pain (NP) is a chronic pain condition caused by injury to the nervous system. Although alternative splicing dysregulation has been implicated in NP, the contribution of RNA-binding proteins (RBPs) to this pro...
Neuropathic pain (NP) is a chronic pain condition caused by injury to the nervous system. Although alternative splicing dysregulation has been implicated in NP, the contribution of RNA-binding proteins (RBPs) to this process remains unclear. We analysed 12 RNA-seq datasets (GSE217932) using the SUVA pipeline to identify splicing alterations in Sham, chronic constriction injury (CCI) and CCI treated with L-tetrahydropalmatine (CCI_THP) groups. Co-expression and co-disturbance analyses were performed to define splicing-associated RBP networks. Key findings were further validated in a CCI rat model by behavioural testing, junction-specific RT-qPCR, immunohistochemistry and immunofluorescence. Distinct splicing profiles were observed among the three groups. Differentially spliced genes were enriched in pathways related to axonogenesis, cell junction assembly and synapse assembly. Several genes, including , showed aberrant splicing in CCI, which was partially reversed by THP treatment. K-means clustering supported a role for THP in restoring synaptic remodelling-related splicing alterations. In addition, splicing was associated with expression, and multiple RBPs, including , were significantly upregulated in CCI. These results were supported by in vivo validation of selected splicing events and protein changes. This study provides a transcriptome-wide view of alternative splicing and RBP dysregulation in NP, and suggests that THP may alleviate neuropathic pain partly by modulating aberrant splicing programs. These findings offer insight into NP mechanisms and identify potential therapeutic targets.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe