RNA Biol [JOURNAL]
Sun
200 papers
Diverse RNAs in human umbilical cord-derived exosomes and their therapeutic potential.
Khezrian A, Sobhi Amjad Z, Khaghani Boroujeni A … +1 more , Shojaeian A
RNA Biol · 2025 Dec · PMID 41222567 · Full text
Exosomes, nanosized extracellular vesicles (30-150 nm) secreted by various cell types, have emerged as crucial mediators of intercellular communication and promising therapeutic agents. This review highlights the diverse...
Exosomes, nanosized extracellular vesicles (30-150 nm) secreted by various cell types, have emerged as crucial mediators of intercellular communication and promising therapeutic agents. This review highlights the diverse RNA cargo of exosomes derived from human umbilical cord mesenchymal stem cells (HucMSC-Exos), including mRNAs, miRNAs, long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), which regulate gene expression and cellular functions in target cells. The mechanisms of exosome biogenesis, release, and uptake are discussed, with emphasis on their ability to cross biological barriers such as the blood - brain barrier. HucMSC-derived exosomes exhibit therapeutic potential in wound healing, angiogenesis, neuroprotection, immunomodulation, and treatment of diseases like Parkinson's, preeclampsia, and renal or hepatic injury. Specific exosomal miRNAs, such as miR-136, miR-335-5p, and miR-1246, demonstrate targeted effects. Additionally, exosomal RNAs show promise as disease biomarkers. Future directions involve standardization, targeted engineering, RNA profiling, clinical trials, and integration into personalized medicine strategies for regenerative therapy.
Abundant A-to-I RNA editing in spermatocytes may suppress transposons to compensate for piRNA downregulation in male germlines.
Duan Y, Xie Q, Ma L … +1 more , Cao Q
RNA Biol · 2025 Dec · PMID 41204419 · Full text
The germline genome serves as a crucial battleground for transposon expansion, as transposons can increase their copy numbers in offspring when activated within germ cells. Unexpectedly, during spermatogenesis, the piRN...
The germline genome serves as a crucial battleground for transposon expansion, as transposons can increase their copy numbers in offspring when activated within germ cells. Unexpectedly, during spermatogenesis, the piRNA pathway, typically responsible for transposon silencing in female germ cells, is significantly downregulated, coinciding with a burst of transposon expression in spermatocytes. This suggests that germ cells might rely on alternative mechanisms for transposon suppression. By leveraging single-cell Smart-seq transcriptomic data, we found that transposon expression, expression, and A-to-I RNA editing efficiency are markedly elevated in spermatocytes. mutant flies exhibit higher testicular TE expression, likely resulting from the loss of editing-mediated suppression. In the absence of a fully functional piRNA pathway in male germline, Adar-mediated RNA editing may act as an alternative mechanism for transposon silencing, highlighting a potential role for Adar in maintaining genome integrity.
RNA-binding antiterminators: regulation of metabolism and pathogenicity in bacteria.
Soussan D, Tahrioui A, de la Haba RR … +4 more , Forge A, Chevalier S, Lesouhaitier O, Muller C
RNA Biol · 2025 Dec · PMID 41188213 · Full text
Antiterminators are essential components of bacterial transcriptional regulation, allowing the control of gene expression in response to fluctuating environmental conditions. Among them, RNA-binding antiterminator protei...
Antiterminators are essential components of bacterial transcriptional regulation, allowing the control of gene expression in response to fluctuating environmental conditions. Among them, RNA-binding antiterminator proteins play a major role in preventing transcription termination by binding to specific RNA sequences. These RNA-binding antiterminators have been extensively studied for their role in regulating various metabolic pathways. However, their function in modulating the physiology of pathogens requires further investigation. This review focuses on RNA-binding proteins displaying CAT (Co-AntiTerminator) or ANTAR (AmiR and NasR Transcription Antitermination Regulators) domains reported in model bacteria. In particular, their structures, mechanism of action, and target genes will be described. The involvement of the antitermination mechanisms in bacterial pathogenicity is also discussed. This knowledge is crucial for understanding the regulatory mechanisms that control bacterial virulence, and opens up exciting prospects for future research, and potentially new alternative strategies to combat infectious diseases.
Emerging roles of long non-coding RNAs in osteoarthritis: from molecular mechanisms to therapeutic opportunities.
Zhao Y, Zhang Y, Peng Y … +5 more , Zheng Z, Li Q, Shen J, Wang H, Liu F
RNA Biol · 2025 Dec · PMID 41186145 · Full text
Long non-coding RNAs (lncRNAs) exert a significant influence on the occurrence and progression of osteoarthritis (OA). LncRNAs are characterized by their multifunctional nature, capable of regulating the expression, tran...
Long non-coding RNAs (lncRNAs) exert a significant influence on the occurrence and progression of osteoarthritis (OA). LncRNAs are characterized by their multifunctional nature, capable of regulating the expression, transcription, translation, and structural function of target genes through various mechanisms, spanning epigenetic, transcriptional, post-transcriptional, and post-translational levels. This review examines the mechanisms and functions of lncRNAs in cell proliferation, differentiation, apoptosis, extracellular matrix (ECM) degradation, and inflammatory responses in chondrocytes, synovial cells, and mesenchymal stem cells (MSCs) from mice and humans associated with OA. We emphasize the integral role of lncRNAs in the OA disease process. Conclusively, we present insights into OA treatment from the perspective of targeting lncRNAs, addressing future development prospects and potential clinical applications.
RNA binding of GAPDH controls transcript stability and protein translation in acute myeloid leukemia.
Shamloo S, Schloßhauer JL, Tiwari S … +9 more , Denise Fischer K, Almolla O, Ghebrechristos Y, Kratzenberg L, Bejoy AM, Aifantis I, Boccalatte F, Wang E, Imig J
RNA Biol · 2025 Dec · PMID 41175344 · Full text
Dysregulation of RNA binding proteins (RBPs) is a hallmark in cancerous cells. In acute myeloid leukaemia (AML) RBPs are key regulators of tumour proliferation. While classical RBPs have defined RNA binding domains, RNA...
Dysregulation of RNA binding proteins (RBPs) is a hallmark in cancerous cells. In acute myeloid leukaemia (AML) RBPs are key regulators of tumour proliferation. While classical RBPs have defined RNA binding domains, RNA recognition and function in AML by non-canonical RBPs (ncRBPs) remain unclear. Given the inherent complexity of targeting AML broadly, our goal was to uncover potential ncRBP candidates critical for AML survival using a CRISPR/Cas-based screening. We identified the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as a pro-proliferative factor in AML cells. Based on cross-linking and immunoprecipitation (CLIP), we are defining the global targetome, detecting novel RNA targets mainly located within 5'UTRs, including GAPDH, RPL13a, and PKM. The knockdown of GAPDH unveiled genetic pathways related to ribosome biogenesis, translation initiation, and regulation. Moreover, we demonstrated a stabilizing effect through GAPDH binding to target transcripts including its own mRNA. The present findings provide new insights on the RNA functions and characteristics of GAPDH in AML.
Circular RNA regulates myogenesis by interacting with mRNA: a novel regulatory axis.
Singh S, Das A, Sahoo G … +1 more , Panda AC
RNA Biol · 2025 Dec · PMID 41170695 · Full text
Many transcriptional and post-transcriptional regulators tightly regulate skeletal muscle myogenesis, including recently discovered circular RNAs (circRNAs). In this study, we used a crosslinking-based sequencing method...
Many transcriptional and post-transcriptional regulators tightly regulate skeletal muscle myogenesis, including recently discovered circular RNAs (circRNAs). In this study, we used a crosslinking-based sequencing method called CLiPP-Seq, in which we performed AMT-mediated Cross-Linking of RNA-RNA duplexes followed by Poly(A) RNA Pulldown and sequencing to identify mRNA-interacting circRNAs in the mRNA samples of mouse C2C12 myoblasts and myotubes. BLAST analysis of the circRNAs with mRNAs identified their potential interacting partners. Interestingly, silencing of the circular RNA () altered the target mRNA (zinc finger protein 143) expression and suppressed the differentiation of C2C12 myoblasts into myotubes. In summary, we identified unexplored mRNA-interacting circRNAs and their possible functions in muscle cell differentiation, specifically the mRNA interaction regulating myogenesis.
Serum-MiR-CanPred: deep learning framework for pan-cancer classification and miRNA-targeted drug discovery.
Patel N, Lawarde A, Surisetti SM … +6 more , Thiruselvam P, Lingasamy P, Sundararajan V, Lulu S S, Salumets A, Modhukur V
RNA Biol · 2025 Dec · PMID 41168129 · Full text
Cancer diagnosis at an early stage is crucial for improving overall health outcomes. However, existing cancer diagnostic techniques are mostly invasive and tend to identify the disease only in its advanced stages. MicroR...
Cancer diagnosis at an early stage is crucial for improving overall health outcomes. However, existing cancer diagnostic techniques are mostly invasive and tend to identify the disease only in its advanced stages. MicroRNAs (miRNAs), which are small non-coding RNAs involved in gene expression regulation, are stable in serum as circulating miRNAs and have potential as non-invasive biomarkers. However, their application in pan-cancer diagnostics and therapeutics is still largely unexplored. We developed Serum-MiR-CanPred, a deep learning framework using a multi-layer perceptron (MLP) trained on serum miRNA expression data from 20,271 samples across 12 cancer types and healthy controls from GEO databases. The model achieves robust pan-cancer classification (AUC = 96.87%, accuracy = 96%) with a consensus set of 88 miRNAs. Validation using external datasets demonstrated its generalizability and clinical potential. SHapley Additive exPlanations (SHAP) identified hsa-miR-5100 as a key biomarker, dysregulated in cancers including lung, bladder, and gastric carcinomas. Pathway analysis linked these miRNAs to cancer-related processes like VEGFA-VEGFR2 signalling. Molecular docking of pre-mir-5100 with rDock, identified AC1MMYR2 as a potential high-affinity ligand, with binding stability confirmed by molecular dynamics simulations using GROMACS In conclusion, Serum-MiR-CanPred integrates explainable AI with molecular modelling, advancing miRNA-based diagnostics and drug discovery for precision oncology.
Targeting RNA-Binding proteins Roquin-1 and Regnase-1 could enhance CAR-iPSC-derived macrophage immunotherapy for solid tumors: a perspective and challenges.
Mirzaei F, Mosaffa Jahromi A, Molavi H … +3 more , Kabelitz D, Kalantar K, Meri S
RNA Biol · 2025 Dec · PMID 41147512 · Full text
Solid tumours present major treatment obstacles because of their immunosuppressive microenvironment and poor response to traditional chimeric antigen receptor (CAR)-based immunotherapies. Recent advances in cellular engi...
Solid tumours present major treatment obstacles because of their immunosuppressive microenvironment and poor response to traditional chimeric antigen receptor (CAR)-based immunotherapies. Recent advances in cellular engineering have introduced CAR-macrophages derived from induced pluripotent stem cells (CAR-iMacs) as a promising approach to get around these obstacles. CAR-iMacs are designed to attack tumours, but their phenotypic plasticity can cause them to transform into M2-like macrophages in the tumour environment (TME), where they may instead suppress immune responses and promote tumour progression and metastasis. Roquin-1 and Regnase-1 are RNA-binding proteins that act as negative regulators of inflammatory genes that contribute to the phenotypic plasticity of macrophages. This perspective highlights a novel approach to augmenting anti-tumour responses of CAR-iMacs by simultaneously knocking out Roquin-1 and Regnase-1 via CRISPR-Cas9 gene editing. This approach drives a shift from an immunosuppressive M2-like state to an M1 state, promoting sustained pro-inflammatory signalling, boosting phagocytic and cytotoxic capabilities within the tumour microenvironment. Addressing a serious constraint in conventional adoptive cell therapies, this dual-targeting platform could provide a potent and scalable immunotherapeutic treatment for solid malignancies.
Enhanced cleavage of genomic using CASX2.
Hodge CA, Donegan NP, Armstrong DA … +2 more , Hayden MS, Howell AL
RNA Biol · 2025 Dec · PMID 41138228 · Full text
Development of novel CRISPR/Cas systems enhances opportunities for gene editing to treat infectious diseases, cancer, and genetic disorders. CasX2 (Cas12e) belongs to the class II CRISPR system derived from , a non-patho...
Development of novel CRISPR/Cas systems enhances opportunities for gene editing to treat infectious diseases, cancer, and genetic disorders. CasX2 (Cas12e) belongs to the class II CRISPR system derived from , a non-pathogenic bacterium present in aquatic and terrestrial soils and offers several advantages as a potential therapeutic CRISPR system over Cas9 (Cas9) and Cas9 (Cas9). These advantages include its smaller size, distinct protospacer adjacent motif (PAM) requirements, staggered cleavage cuts that promote homology-directed repair, and the absence of pre-existing immunity in humans. We compared the cleavage efficiency and double-stranded break repair characteristics between CasX2 and CasX2, a recently generated CasX2 variant with three amino acid substitutions, for targeting , a gene that encodes the CCR5 receptor important for HIV-1 infection. Two single guide RNAs (sgRNAs) were designed that flank the 32 bases deleted in the natural mutation. Nanopore sequencing demonstrated that CasX2 using sgRNAs with spacers of 17 nucleotides (nt), 20 nt or 23 nt in length were ineffective at cleaving genomic . In contrast, CasX2 using sgRNAs with 20 nt and 23 nt spacer lengths, enabled cleavage of genomic . Structural modelling indicated that two of the CasX2 amino acid substitutions enhanced sgRNA-DNA duplex stability, while the third improved DNA strand alignment within the catalytic site. These structural changes likely underlie the increased activity of CasX2 in cellular gene excision. In sum, CasX2 consistently outperformed native CasX2 across all assays and represents a superior gene-editing platform for therapeutic applications.
EIF4A3-induced circFAT1 promotes high glucose-induced podocyte damage via miR-30e-5p/SOX4 axis.
Huang Y, Liu Y, Yang M … +2 more , Zhao L, Chen M
RNA Biol · 2025 Dec · PMID 41114741 · Full text
Podocyte injury significantly contributes to glomerular filtration dysfunction and albuminuria in diabetic nephropathy (DN). Circular RNAs, particularly circFAT1 (hsa_circ_0001461), have emerged as influential regulators...
Podocyte injury significantly contributes to glomerular filtration dysfunction and albuminuria in diabetic nephropathy (DN). Circular RNAs, particularly circFAT1 (hsa_circ_0001461), have emerged as influential regulators in pathological processes. This research focused on exploring the function of hsa_circ_0001461 in high glucose (HG)-induced podocyte damage and the associated underlying mechanism. Here, we demonstrate that circFAT1 is significantly upregulated in HPCs under HG conditions. Inhibition of circFAT1 led to decreased podocyte migration and a restoration of differentiation markers, along with a reduction in mesenchymal markers. Mechanistically, circFAT1 was found to inhibit miR-30e-5p, resulting in enhanced SOX4 expression, which promoted epithelial-mesenchymal transition and migration in podocytes. Moreover, we identified EIF4A3 as a crucial regulator of circFAT1 biogenesis under hyperglycaemic conditions. Importantly, elevated levels of circFAT1 were also detected in DN patients, correlating with increased albuminuria and serum creatinine. In conclusion, this study elucidates the critical role of circFAT1 in HG-induced podocyte injury through the miR-30e-5p/SOX4 signalling pathway. The findings suggest that targeting circFAT1 May offer a potential strategy for DN intervention.
Coordination of the Fe-S cluster biogenesis network by the sRNA RyhB in .
Prévost K, Vega Valle CD, Normand MH … +5 more , Béliveau-Caron AL, Poirier S, Lalaouna D, Chénard T, Massé E
RNA Biol · 2025 Dec · PMID 41097808 · Full text
Iron (Fe) plays critical roles as enzyme cofactor involved in key biological processes but can also lead to toxicity by catalysing the formation of highly damaging reactive oxygen species. To stabilize Fe and perform cat...
Iron (Fe) plays critical roles as enzyme cofactor involved in key biological processes but can also lead to toxicity by catalysing the formation of highly damaging reactive oxygen species. To stabilize Fe and perform catalysis, most organisms rely on Fe-S clusters, which are fundamental and evolutionary ancient cofactors. In , two distinct pathways for the biosynthesis of Fe-S cluster exist: the three-part (ISC-HSC) operon and the (SUF) operon. The section of the ISC-HSC operon is regulated at the promoter level by the IscR transcription factor and post-transcriptionally by the small RNA (sRNA) RyhB. The SUF operon is regulated by a combination of transcription factors, including the Fe-sensing Fur, the Fe-S using IscR, and the oxidative stress responsive OxyR. Here, we show evidence that the sRNA RyhB regulates the part of the ISC-HSC operon as well as part of the SUF operon. RyhB orchestrates a complex pattern of expression of the operon during Fe starvation. This results in increased level of and constant expression of , encoding the scaffold for Fe-S cluster formation. However, the third part of the operon, , encoding a chaperone that facilitates Fe-S cluster transfer, is repressed by RyhB during Fe starvation. Furthermore, RyhB represses part of the transcript, which counteracts Fur derepression. Overall, RyhB represses both ISC and SUF systems under iron starvation, to reduce Fe-S biogenesis under such limiting conditions.
Precursor RNA structural patterns at SF3B1 mutation sensitive cryptic 3' splice sites.
Herbert A, Hatfield A, Randazza A … +3 more , Miyamoto V, Palmer K, Lackey L
RNA Biol · 2025 Dec · PMID 41058062 · Full text
SF3B1 is a core component of the spliceosome involved in branch point recognition and 3' splice site selection. The SF3B1 K700E mutation (lysine to glutamic acid) is common in myelodysplastic syndrome and other blood dis...
SF3B1 is a core component of the spliceosome involved in branch point recognition and 3' splice site selection. The SF3B1 K700E mutation (lysine to glutamic acid) is common in myelodysplastic syndrome and other blood disorders. SF3B1 K700E mutants utilize novel cryptic 3' splice sites; however, the properties distinguishing SF3B1-sensitive splice junctions from other alternatively spliced junctions are unknown. We identify a subset of 192 cryptic 3' splice junctions with significantly altered use in SF3B1 K700E cells, termed SF3B1-sensitive cryptic 3' splice sites, and 2800 cryptic 3' splice sites used in SF3B1 wild-type, termed SF3B1-resistant. We find that SF3B1-sensitive cryptic 3' splice sites are embedded in extended polypyrimidine tracts. Furthermore, canonical splice sites paired to SF3B1-sensitive cryptic 3' splice sites are significantly weaker than canonical 3' splice sites paired to SF3B1-resistant cryptic 3' splice sites. We test whether SF3B1-sensitive splice sites are structurally different from SF3B1-resistant 3' splice sites using chemical probing. We develop experimental RNA structure data for 83 SF3B1-sensitive junctions and 39 SF3B1-resistant junctions. We find that the pattern of structural accessibility at the NAG splicing motif in cryptic and canonical 3' splice sites is similar. However, the magnitude of accessibility differences is less in paired SF3B1-sensitive splice sites than in paired SF3B1-mutant splice sites. Additionally, SF3B1-sensitive splice junctions are more flexible than SF3B1-resistant junctions. Our results suggest that SF3B1-sensitive splice junctions have unique structure and sequence properties, containing poorly differentiated, weak splice sites that lead to altered 3' splice site recognition in the presence of SF3B1 mutation.
DeepRNA-Reg: a deep-learning based approach for comparative analysis of CLIP experiments.
Sekhon H, Kageyama R, Sprenkle NT … +4 more , Happ HC, Wigton EJ, Pua HH, Ansel KM
RNA Biol · 2025 Dec · PMID 41055236 · Full text
DeepRNA-Reg employs advances in deep learning to enable high-fidelity comparative analysis of paired datasets of high-throughput sequencing of RNA isolated by crosslinking immunoprecipitation (HITS-CLIP). In a HITS-CLIP...
DeepRNA-Reg employs advances in deep learning to enable high-fidelity comparative analysis of paired datasets of high-throughput sequencing of RNA isolated by crosslinking immunoprecipitation (HITS-CLIP). In a HITS-CLIP experimental paradigm where Ago2 targeting is selectively perturbed via gene knock-out of a microRNA cluster, DeepRNA-Reg offers a superior prediction set when compared with the current best prescription for differential HITS-CLIP analysis. Furthermore, DeepRNA-Reg predictions adhered better to the ground-truth of RNA primary and secondary structural motifs that enable miRNA-mediated targeting of RNA. In the tested data sets, DeepRNA-Reg uncovered novel mediators in the mechanism of microRNA-mediated restraint of type-2 immunity in T-Helper 2 cells. In a comparative analysis, DeepRNA-Reg predictions show greater translatability across distinct biological milieux, offering prediction sets with wide applicability for investigators.
Altering rRNA 2'O-methylation pattern during neuronal differentiation is regulated by FMRP.
Ninochka D'Souza M, Gowda NKC, Hariharan N … +3 more , Qadri SW, Palakodeti D, Muddashetty RS
RNA Biol · 2025 Dec · PMID 41042002 · Full text
The Fragile X Messenger Ribonucleoprotein (FMRP) is a selective RNA-binding protein that localizes to the cytoplasm and the nucleus. The loss of FMRP results in Fragile X Syndrome (FXS), an autism spectrum disorder. FMRP...
The Fragile X Messenger Ribonucleoprotein (FMRP) is a selective RNA-binding protein that localizes to the cytoplasm and the nucleus. The loss of FMRP results in Fragile X Syndrome (FXS), an autism spectrum disorder. FMRP interacts with ribosomes and regulates the translation of mRNAs essential for neuronal development and synaptic plasticity. However, the biochemical nature of this translation regulation is unknown. Here, we report that a potential feature of FMRP-mediated translation regulation during neuronal differentiation is the modulation of 2'-O-methylation of ribosomal RNA. 2'O-methylation, facilitated by C/D box snoRNAs in the nucleus, is a major epitranscriptome mark on rRNA, essential for ribosome assembly and function. We found that FMRP influences a distinct rRNA 2'O-Methylation pattern across neuronal differentiation. We show that in H9 ESCs, FMRP interacts with a selected set of C/D box snoRNA in the nucleus, resulting in the generation of ribosomes with a distinct pattern of rRNA 2'O-Methylation. This epitranscriptome pattern on rRNA undergoes a significant change during the differentiation of ESCs to neuronal precursors and cortical neurons. ESCs exhibit substantial levels of hypomethylated residues on rRNA, which progressively decrease in neuronal precursors and post-mitotic cortical neurons. This reduction correlates with changes in global protein synthesis across different stages of differentiation. Importantly, this stepwise change in the 2'O-methylation pattern during neuronal differentiation is altered in the absence of FMRP, which could impact neuronal development and contribute to dysregulated protein synthesis observed in Fragile X Syndrome.
suppresses hepatocellular carcinoma progression via targeting .
Lin J, Cai Y, Chen Z … +2 more , Ma J, Zhao K
RNA Biol · 2025 Dec · PMID 41037059 · Full text
Aberrantly expressed microRNA-4484 () has recently garnered attention for its involvement in human diseases, but its specific role in hepatocellular carcinoma (HCC) remains largely unexplored. This study investigates the...
Aberrantly expressed microRNA-4484 () has recently garnered attention for its involvement in human diseases, but its specific role in hepatocellular carcinoma (HCC) remains largely unexplored. This study investigates the function of in HCC progression and its regulatory interaction with . Analysis of the data from the TCGA-LIHC database revealed that expression is significantly downregulated in HCC tissues, with lower levels correlating with worse prognosis. experiments confirmed that expression is lower in HCC cell lines compared to a normal liver cell line. Functional assays demonstrated that overexpression via a mimic suppressed cell proliferation and induced G1 phase arrest, whereas inhibition promoted proliferation and facilitated cell cycle progression from G1 to S and G2 phases. Additionally, expression was significantly upregulated in HCC tissues and cell lines, exhibiting an inverse correlation with levels. Dual-Luciferase Reporter Assays confirmed that directly binds to , thereby regulating its expression and influencing cell proliferation and cell cycle progression. , subcutaneous intratumoral injection of the mimic in nude mice significantly inhibited HCC tumour growth. These findings highlight as a potential tumour suppressor in HCC through its direct targeting of , underscoring its promise as a therapeutic target for HCC treatment.
E2-regulated transcriptome complexity revealed by long-read direct RNA sequencing: from isoform discovery to truncated proteins.
Dioken DN, Ozgul I, Yilmazbilek I … +9 more , Almeric E, Eroglu IC, Cicek M, Yilmaz UC, Karagozoglu D, Cicek E, Karaca E, Can T, Erson-Bensan AE
RNA Biol · 2025 Dec · PMID 40965441 · Full text
Oestrogen receptor alpha (ERα)-positive (ER+) breast cancers are driven by the binding of 17β-oestradiol (E2) to ERα, which transcriptionally regulates target genes. Although microarrays and conventional RNA sequencing h...
Oestrogen receptor alpha (ERα)-positive (ER+) breast cancers are driven by the binding of 17β-oestradiol (E2) to ERα, which transcriptionally regulates target genes. Although microarrays and conventional RNA sequencing have identified E2 target genes, pre-designed probes and short read lengths are limited in their ability to accurately capture complex transcript structures. Long-read sequencing offers a solution by spanning entire transcripts, providing a more complete view of the transcriptome. Here, we employed nanopore long-read direct RNA sequencing (DRS) complemented with 3'-end sequencing, in vitro experiments, and deep learning-based protein modelling to explore the landscape of the E2-responsive transcriptome and protein level implications. Our analysis revealed a range of E2-responsive non-coding and coding isoforms, including intronically polyadenylated (IPA) mRNAs. One of these IPA isoforms was detected for TLE1, which assists ERα-chromatin interactions for a subset of E2 targets. The IPA isoform produces a C-terminus truncated protein that lacks the WDR interaction domain but retains dimerization/tetramerization capacity through its intact N-terminal Q-domain. Structural modelling and protein-based assays confirmed the dimerization potential and nuclear localization of the truncated protein. Functional assays showed that the overexpression of truncated TLE1 reduced the E2-induced upregulation of and , E2-responsive genes, thereby disrupting transcriptional regulation. Importantly, a lower IPA isoform ratio is associated with worse survival in ER+ breast cancers, highlighting clinical relevance. Our study revealed new layers of complexity in the E2-regulated transcriptome, providing insights into truncated proteins. These findings contribute to a deeper understanding of gene regulation and may help the development of new therapeutic strategies.
MicroRNA-mediated regulation of proliferation, lineage differentiation, and apoptosis in neural stem cells.
Lee Y, Boschian C, Ko K
RNA Biol · 2025 Dec · PMID 40924462 · Full text
Neural stem cells (NSCs) are multipotent stem cells with self-renewal capacity, able to differentiate into all neural lineages of the central nervous system, including neurons, oligodendrocytes, and astrocytes; thus, the...
Neural stem cells (NSCs) are multipotent stem cells with self-renewal capacity, able to differentiate into all neural lineages of the central nervous system, including neurons, oligodendrocytes, and astrocytes; thus, their proliferation and differentiation are essential for embryonic neurodevelopment and adult brain homoeostasis. Dysregulation in these processes is implicated in neurological disorders, highlighting the need to elucidate how NSCs proliferate and differentiate to clarify the mechanisms of neurogenesis and uncover potential therapeutic targets. MicroRNAs (miRNAs) are small, post-transcriptional regulators of gene expression involved in many aspects of nervous system development and function. Multiple studies have shown that miRNAs control the balance between self-renewal and differentiation during development through transcriptional networks and fine-tuned signalling pathways. They also regulate key biological processes, including cell fate determination, developmental timing, neurogenesis, gliogenesis, and apoptosis. Transcriptomic analyses and high-resolution profiling have revealed temporally and spatially restricted miRNA expression patterns in NSCs and their progeny, suggesting highly context-dependent regulatory functions. Here, we provide an integrated overview of recent advances in miRNA biology relevant to NSC maintenance and lineage specification, with a focus on the mechanistic understanding of miRNA roles in neuronal differentiation, glial development, and programmed cell death across neural development.
Direct and indirect effects of spliceosome disruption compromise gene regulation by nonsense-mediated mRNA decay.
Embree CM, Paul D, Stephanou A … +1 more , Singh G
RNA Biol · 2025 Dec · PMID 40856040 · Full text
Pre-mRNA splicing, carried out in the nucleus by a large ribonucleoprotein machine known as the spliceosome, is functionally and physically coupled to the mRNA surveillance pathway in the cytoplasm called nonsense-mediat...
Pre-mRNA splicing, carried out in the nucleus by a large ribonucleoprotein machine known as the spliceosome, is functionally and physically coupled to the mRNA surveillance pathway in the cytoplasm called nonsense-mediated mRNA decay (NMD). The NMD pathway monitors for premature translation termination, which can result from alternative splicing, by relying on the exon junction complex (EJC) deposited on exon-exon junctions by the spliceosome. Recently, multiple genetic screens in human cell lines have identified numerous spliceosome components as putative NMD factors. Using publicly available RNA-seq datasets from K562 and HepG2 cells depleted of 18 different spliceosome components, we found that natural NMD-targeted mRNA isoforms were upregulated when catalytic spliceosome members were reduced. While some of this increase could be due to widespread pleiotropic effects of spliceosome dysfunction (e.g. reduced expression of NMD factors due to missplicing of their mRNAs), we identified that AQR, SF3B1, SF3B4, and CDC40 may have a more direct role in NMD. We also tested the hypothesis that increased production of novel NMD substrates may overwhelm the pathway to find a direct correlation between the amount of novel NMD substrates detected and the degree of NMD inhibition observed. Finally, similar transcriptome alterations and NMD substrate upregulation were observed in cells treated with spliceosome inhibitors and in cells derived from retinitis pigmentosa patients with mutations in and . Overall, our results show that regardless of the cause, spliceosome disruption upregulates a broad set of NMD targets, which could contribute to cellular dysfunction in spliceosomopathies.
Opposing mechanisms by which miRNAs mediate distinct Nrf1 and Nrf2 regulation of epithelial-mesenchymal transition in hepatocellular carcinoma.
Chen J, Feng J, Zhu Y … +2 more , Hu S, Zhang Y
RNA Biol · 2025 Dec · PMID 40836845 · Full text
Accumulation of various genetics and epigenetics alterations are accepted to result in the initiation and progression of hepatocellular carcinoma (HCC), and its high metastasis is viewed as a critical bottleneck leading...
Accumulation of various genetics and epigenetics alterations are accepted to result in the initiation and progression of hepatocellular carcinoma (HCC), and its high metastasis is viewed as a critical bottleneck leading to its treatment failure. Amongst them, the microRNAs arising from the lack of the antioxidant transcription factor Nrf2 lead to cancer metastasis. However, much less is known about the regulation of microRNAs by Nrf1, even though it acts as an essential determinon of cell homoeostasis by governing the transcriptional expression of those driver genes contributing to the EMT involved in its metastasis. In this study, distinct EMT phenotypes resulted from specific knockouts of Nrf1 and Nrf2 in HepG2 cells, as accompanied by their differential migratory and invasive capabilities. The -leading EMT results from a significant decrease in the epithelial CDH1 expression, plus another increased expression of the mesenchymal CDH2. Such distinct phenotypes of from cell lines were also attributable to differential regulation of two key microRNAs, i.e. and . Further experiments also unravelled that Nrf1 activates the expression, directly targeting for the inhibition of , leading to CDH1 activation but with CDH2 inhibition insomuch as to prevent the process of EMT. By contrast, Nrf2 inhibits the expression, relieving its inhibitory effect on MMP15 and MMP17 to promote the EMT. Collectively, these results demonstrate that the EMT of HCC is likely prevented by Nrf1 the miR-3187-3p signalling to SNAI1-CDH1/2 axis, but conversely promoted by Nrf2 through the miR-1247-5p-MMP15/17 signalling axis.
Time-resolved miRNA-mRNA integrated analysis reveals the miRNA-mRNA networks underlying plasma membrane damage-dependent senescence and DNA damage response-dependent senescence in WI-38 normal human fibroblasts.
Chiu Y, Ishida R, Moriyama Y … +2 more , Grašič J, Kono K
RNA Biol · 2025 Dec · PMID 40843545 · Full text
Cellular senescence is a stable cell cycle arrest associated with upregulated inflammatory responses. Senescent cells contribute to various pathological and physiological processes including organismal ageing and cancer....
Cellular senescence is a stable cell cycle arrest associated with upregulated inflammatory responses. Senescent cells contribute to various pathological and physiological processes including organismal ageing and cancer. Cellular senescence can be induced by various cellular stresses including DNA damage, telomere shortening, oncogene activation, and epigenetic alterations. We have shown that plasma membrane damage can also induce cellular senescence. However, common and specific molecular mechanisms among different senescent cell subtypes remain unknown. MicroRNAs (miRNAs) regulate mRNA and rewire gene expression profiles, contributing to multiple processes including cellular senescence. Here, we performed time-resolved miRNA sequencing and compared the results with mRNA sequencing results using cells experiencing plasma membrane damage-dependent senescence (PMD-Sen) and cells undergoing DNA damage response-dependent senescence (DDR-Sen). We found 65 miRNAs that are differentially regulated in PMD-Sen, contributing to 2,495 miRNA-mRNA pairs. Moreover, PMD-Sen and DDR-Sen shared 41 miRNAs across their sets of miRNA-mRNA pairs. Notably, miR-155-5p emerged as the miRNA with the largest number of shared miRNA-mRNA pairs that exhibit a highly negative correlation. These results highlight miR-155-5p as the potential key regulator of PMD-Sen and DDR-Sen.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe