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Contrasting regulation of protein-coding genes and lncRNA homeologs in allotetraploid Coffea arabica.

A chromosome-level Bourbon assembly revealed that protein-coding homeologs are predominantly co-regulated between subgenomes. In contrast, intergenic lncRNAs display a modest, but statistically consistent bias toward subgenome E across diverse developmental and stress contexts. Coffea arabica is an allotetraploid species derived from natural hybridization between C. canephora and C. eugenioides, which contributed the C and E subgenomes, respectively. This genomic origin poses major challenges for genome assembly, annotation, and the interpretation of gene regulation. In this study, a high-quality genome assembly of C. arabica was generated and annotated, with particular emphasis on identifying protein-coding genes and intergenic long non-coding RNAs (lincRNAs). Homeologous relationships between genes from the C and E subgenomes were established, providing a robust framework to investigate subgenomic conservation and regulatory divergence. Using an extensive collection of publicly available RNA-seq libraries spanning multiple developmental stages, tissues, and environmental conditions, the relative transcriptional contribution of each subgenome was evaluated. On a global scale, gene expression was largely balanced between subgenomes, with no consistent evidence of subgenome dominance. While protein-coding genes showed comparable regulatory behavior across subgenomes, lincRNAs exhibited a more asymmetric expression pattern, suggesting higher subgenome-specific expression that is interpreted here as a consistent directional tendency rather than as evidence of subgenome dominance. Together, these results provide new insights into the regulatory architecture of the C. arabica genome and establish a foundational genomic and transcriptomic resource for future functional studies and crop improvement efforts.

Coffea

Long non-coding RNAs link DNA methylation to immune regulatory networks in bovine subclinical mastitis.

Long non-coding RNAs (lncRNAs) are emerging as important regulators of inflammatory and immune signaling, yet their contribution to bovine subclinical mastitis remains poorly defined. Here, we characterized the lncRNA expression landscape associated with disease in milk somatic cells of healthy and subclinical mastitic Vrindavani cattle. We identified 11,403 high-confidence lncRNAs, of which 104 were differentially expressed in subclinical mastitis (adjusted P&#x2009;<&#x2009;0.05; |log2FC| &#x2265; 1), with the vast majority upregulated in mastitic samples. Predicted cis- and trans-associated target analyses identified 637 non-redundant genes, and KEGG analysis identified 8 significantly enriched cis-associated pathways and 152 significantly enriched trans-associated pathways (adjusted P&#x2009;<&#x2009;0.05), predominantly enriched for immune and inflammation-related pathways. These findings prioritized a subset of mastitis-associated lncRNAs for subsequent methylation and interaction-network analyses. A subset of these lncRNAs further overlapped differentially methylated regions (DMRs), suggesting a potential association between lncRNA expression changes and DNA methylation alterations. Integration of lncRNA-miRNA and miRNA-mRNA interactions identified lncRNA-miRNA-mRNA interaction networks involving DMR-associated lncRNAs. Among the prioritized candidates, MSTRG.28878.1 showed overlap with a hypomethylated promoter-associated DMR, increased expression, and multiple connections within the predicted interaction network. Together, these findings identify candidate lncRNAs, methylation-associated loci, and predicted molecular interactions associated with bovine subclinical mastitis and provide a resource for future functional investigation of candidate non-coding RNA-associated mechanisms in disease.

Animals

Whole transcriptome sequencing analyses of islets reveal ncRNA regulatory networks underlying impaired insulin secretion and increased &#x3b2;-cell mass in high fat diet-induced diabetes mellitus.

AIM: Our study aims to identify novel non-coding RNA-mRNA regulatory networks associated with &#x3b2;-cell dysfunction and compensatory responses in obesity-related diabetes. METHODS: Glucose metabolism, islet architecture and secretion, and insulin sensitivity were characterized in C57BL/6J mice fed on a 60% high-fat diet (HFD) or control for 24 weeks. Islets were isolated for whole transcriptome sequencing to identify differentially expressed (DE) mRNAs, miRNAs, IncRNAs, and circRNAs. Regulatory networks involving miRNA-mRNA, lncRNA-mRNA, and lncRNA-miRNA-mRNA were constructed and functions were assessed through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. RESULTS: Despite compensatory hyperinsulinemia and a significant increase in &#x3b2;-cell mass with a slow rate of proliferation, HFD mice exhibited impaired glucose tolerance. In isolated islets, insulin secretion in response to glucose and palmitic acid deteriorated after 24 weeks of HFD. Whole transcriptomic sequencing identified a total of 1324 DE mRNAs, 14 DE miRNAs, 179 DE lncRNAs, and 680 DE circRNAs. Our transcriptomic dataset unveiled several core regulatory axes involved in the impaired insulin secretion in HFD mice, such as miR-6948-5p/Cacna1c, miR-6964-3p/Cacna1b, miR-3572-5p/Hk2, miR-3572-5p/Cckar and miR-677-5p/Camk2d. Additionally, proliferative and apoptotic targets, including miR-216a-3p/FKBP5, miR-670-3p/Foxo3, miR-677-5p/RIPK1, miR-802-3p/Smad2 and ENSMUST00000176781/Caspase9 possibly contribute to the increased &#x3b2;-cell mass in HFD islets. Furthermore, competing endogenous RNAs (ceRNA) regulatory network involving 7 DE miRNAs, 15 DE lncRNAs and 38 DE mRNAs might also participate in the development of HFD-induced diabetes. CONCLUSIONS: The comprehensive whole transcriptomic sequencing revealed novel non-coding RNA-mRNA regulatory networks associated with impaired insulin secretion and increased &#x3b2;-cell mass in obesity-related diabetes.

Mice

LINC00922 regulates epithelial-mesenchymal transition, invasive and migratory capacities in breast cancer through promoting NKD2 methylation.

Breast cancer ranks as the major reason for mortality in women populations, accounting for 23% of all cancer deaths. One in every three Asian women encounters the risk of this cancer in their lifetime. Long intergenic non-coding RNAs (lincRNAs) have emerged as tumor promoters and suppressors. The molecular mechanism of breast cancer remains elusive. Therefore, the current study aimed to explore the role lincRNA LINC00922 plays in the development of breast cancer. Breast cancer tissues and adjacent tissues were obtained from 109 patients with breast cancer. The RNA extraction and quantification and immunohistochemical staining characterized the high expression of LINC00922 and low expression of NKD2 in breast cancer tissues in comparison to its adjacent counterparts. Furthermore, the ectopic expression and knockdown experiments were conducted to figure out the in vivo and in vitro effects of LINC00922 on breast cancer progression. The ectopically expressed LINC00922 activated the Wnt signaling pathway, promoted epithelial-mesenchymal transition, cell proliferative, invasive and migratory capacities, tumor growth and metastasis. Additionally, the RIP and ChIP assay identified that LINC00922 recruited DNMT1, DNMT3A and DNMT3B proteins in the promoter region of NKD2 to promote NKD2 promoter methylation, thus reducing the NKD2 expression. Moreover, the Wnt signaling pathway was activated subsequent to NKD2 silencing, which was reversed by LINC00922 silencing. Lastly, the anti-oncogenic effects of LINC00922 inhibition was antagonized after NKD2 knocked down. The current study provides evidence that LINC00922 acts as a tumor promoter by promoting NKD2 methylation. Hopefully, it provides a novel potential gene target for the treatment of breast cancer.

Adaptor Proteins, Signal Transducing

Identifying Co-Expressed lncRNAs Correlated With Traits of Interest in an Animal Model for Metabolic Diseases in Humans.

Nutrigenomics investigates how nutrients modulate gene expression. Among them, fatty acids (FA) play important roles in regulating gene transcription, while long non-coding RNAs (lncRNAs) may be associated with gene regulation and metabolic diseases. This study aimed to analyze the hepatic transcriptome of pigs, a species frequently used as a model for nutrigenomic studies, to identify novel lncRNAs and their potential target genes in response to diets containing different sources of FA. Seventy-two pigs were fed four diets supplemented with 1.5% soybean oil (control), 3% canola oil, 3% fish oil, and 3% soybean oil. RNA sequencing of liver samples was performed to identify novel lncRNAs. Weighted Gene Co-expression Network Analysis (WGCNA) was used to identify modules associated with phenotypic traits related to lipid metabolism and inflammation. Functional enrichment analyses were then conducted to annotate genes within these modules using Gene Ontology (GO) terms and to assess overlap with Quantitative Trait Loci (QTL). The results revealed 106 novel lncRNAs potentially regulating genes associated with lipid metabolism and immune responses in pigs fed diets with different FA sources. These findings enhance understanding of the regulatory role of lncRNAs in pigs and reinforce their relevance as models for human metabolic diseases.

Animals

A novel deep learning-driven framework for improving lncRNA comprehensive annotation with LncADeep 2.0.

MOTIVATION: Long non-coding RNAs (lncRNAs) have emerged as crucial players in diverse physiological and pathological processes, yet the biological mechanisms of the vast majority of lncRNAs remain elusive. To fill this gap, it is necessary to improve the accuracy of lncRNA identification and functional annotation. RESULTS: Here, we introduce LncADeep 2.0, an integrated deep learning framework designed to meet these needs. In the identification module, LncADeep 2.0 incorporated novel peptide features along with sequence and structural information, demonstrating superior performance over our previous LncADeep and other existing tools on both annotated transcripts from GENCODE and RNA-seq data. For functional annotation, LncADeep 2.0 leveraged lncRNA-centric interaction networks and gene ontology terms through the transfer learning strategy to achieve robust annotation performance with limited functional data. Compared to LncADeep, LncADeep 2.0 could accurately elucidate the general functions of given lncRNA sequences, predict tissue- or cell-type-specific functions from bulk and single-cell RNA-seq data, and establish connections between tumor-associated lncRNAs and genomic markers. Overall, LncADeep 2.0 stands out as an efficient and reliable tool for lncRNA identification and functional annotation across a wide spectrum of biological processes. AVAILABILITY AND IMPLEMENTATION: LncADeep 2.0 is available for use at https://github.com/Jefferson-Chou/LncADeep2 and https://doi.org/10.5281/zenodo.17164767.

RNA, Long Noncoding

Constructing epigenetic regulatory landscapes of plant lncRNAs-an exploration utilizing the novel specialized platform PERlncDB.

Long non-coding RNAs (lncRNAs), once overlooked as transcriptional byproducts, are now recognized for their crucial roles in plant growth, development, and stress responses, with increasing focus on their epigenetic regulation. However, studies investigating epigenomic signals to explore the functions of lncRNAs in plants remain relatively limited. This study collected a comprehensive dataset of over 160&#x2009;000 high-quality lncRNAs from 19 representative plant species and integrated 6715 ChIP-seq, BS-seq, and RNA-seq datasets to analyze epigenomic patterns at lncRNA loci. Results showed elevated DNA methylation in lncRNA regions. The highest levels occurred in transposable element-associated lncRNAs. Additionally, activating histone modifications at lncRNA loci showed tissue specificity, with epigenetic preferences differed from those at protein-coding gene (PCG) loci. Differential site analysis in epigenetic mutants further highlighted the selective regulation of lncRNA loci by specific epigenetic factors. To facilitate research, we developed PERlncDB, a platform that provides species-specific lncRNA browsing, epigenetic annotation, cross-species conservation analysis, and visualization of epigenomic landscapes. Case studies on MARS and LINC-AP2 emphasized the platform's utility. Conserved epigenetic mechanisms regulating lncRNAs across species, exemplified by a syntenic conserved MET1-regulated lncRNA pair in Arabidopsis and tomato, suggested the stability of regulatory mechanisms underlying lncRNA functions. This work provides critical insights and resources for understanding plant lncRNA epigenetic regulation.

RNA, Long Noncoding

Epigenetics and In Silico Transcriptome Analysis of Pediatric Acute Myeloid Leukemia.

Pediatric acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy that accounts for about 15%-20% of childhood leukemias. Despite therapeutic advances, relapses remain common, and survival for high-risk patients is below 60%. Unlike adult AML, pediatric AML displays distinct genetic mutations, including FLT3-ITD, NPM1, KMT2A rearrangements, and core-binding factors (CBF) fusions, as well as extensive epigenetic dysregulation. Aberrant DNA methylation, histone modifications, and altered non-coding RNA expressions disrupt hematopoietic differentiation and activate oncogenic transcriptional networks. Recent advances in silico transcriptomic analysis have transformed the study of pediatric AML by integrating gene expression and epigenetic data to identify molecular drivers and regulatory networks. Computational RNA-seq pipelines and pathway analyses have highlighted key epigenetic regulators, including DNMT3A, TET2, and HDACs, as potential therapeutic targets. Multi-omics approaches combining transcriptomic, methylomic, and chromatin accessibility data are increasingly used to define biomarkers for diagnosis, prognosis, and therapeutic response. This review provides a comprehensive overview of the molecular and epigenetic landscape of pediatric AML, emphasizing the power of in silico transcriptome analysis to uncover disease mechanisms, refine patient stratification, and guide the development of precision-based epigenetic therapies aimed at improving long-term outcomes in children with AML.

Humans

Cancer-associated fusion transcripts: mechanisms, functional roles, and clinical implications.

Fusion transcripts are hybrid RNA molecules generated through genomic rearrangements or RNA-level fusion mechanisms. They represent important molecular features of many cancers and can function as oncogenic drivers, diagnostic biomarkers, prognostic indicators, and therapeutic targets. Since the discovery of the BCR::ABL1 fusion in chronic myeloid leukemia, numerous cancer-associated fusion transcripts have been identified across hematologic malignancies and solid tumors. These fusion events encompass diverse biological mechanisms, including constitutively active kinases, aberrant transcription factors, epigenetic regulators, and non-coding fusion RNAs. This review summarizes current knowledge of the mechanisms underlying fusion transcript formation, including genomic rearrangement-dependent and rearrangement-independent processes, as well as fusion circular RNAs. The functional roles of fusion transcripts in cancer biology and their clinical relevance as diagnostic, prognostic, and predictive biomarkers are discussed. In addition, recent advances in fusion transcript detection and characterization are reviewed, including next-generation sequencing, long-read sequencing, single-cell approaches, artificial intelligence-assisted computational methods, and CRISPR/Cas9-mediated strategies for functional modeling and functional validation of fusion transcripts. Despite the rapid expansion of fusion transcript catalogs, the biological and clinical significance of most identified fusion events remains incompletely understood. Future progress will depend on integrating advanced sequencing technologies, artificial intelligence-assisted computational prioritization, and systematic functional validation to distinguish clinically actionable fusion transcripts from biologically neutral events. Such multidisciplinary approaches will be essential for translating fusion transcript research into precision oncology and improving cancer diagnosis, patient stratification, and targeted therapy.

Humans

Non-coding RNAs as regulators of chromosomal instability in breast cancer.

Breast cancer is a highly heterogeneous disease characterized by extensive genomic and chromosomal instability (CIN), a hallmark that drives tumor evolution, intratumoral heterogeneity, therapeutic resistance, and poor clinical outcomes. Increasing evidence indicates that non-coding RNAs (ncRNAs) are important regulators of genome maintenance and chromosome stability. However, their specific contributions to CIN and the strength of the available evidence remain incompletely understood. This review examines the role of the major ncRNA classes, including circular RNAs, microRNAs, PIWI-interacting RNAs, small nucleolar RNAs, and long non-coding RNAs, in the regulation of CIN-related processes in breast cancer. We discuss the molecular mechanisms by which these ncRNAs regulate key pathways involved in CIN, while critically evaluating the strength of the experimental evidence supporting their functional roles. We also examine their associations with distinct breast cancer molecular subtypes and assess their potential as biomarkers and therapeutic targets, highlighting current limitations and knowledge gaps that hinder clinical translation. Collectively, the available evidence supports an emerging role for ncRNAs as regulators of CIN while underscoring the need for further mechanistic and subtype-specific studies to validate their clinical utility.

DNA repair

Expression analysis of LINC00671 and LINC01913 long non-coding RNAs in gastric cancer patients and their correlation with EMT markers.

BACKGROUND: Long-chain non-coding RNAs (lncRNAs) play various roles in the regulation of gene expression at the levels of transcription and translation, and epigenetic modification. Dysregulation of lncRNAs is associated with various malignancies, including cancer. lncRNAs have been demonstrated to regulate critical biological processes in cancer cells, such as apoptosis, proliferation, migration, and invasion. They also play essential roles in the development of gastric cancer (GC). However, the clinical significance and biological function of many lncRNAs remain unexplored in GC progression. This study aimed to evaluate the expression profiles of LINC00671 and LINC01913 in GC patients and investigate their correlation with epithelial-to-mesenchymal transition (EMT) markers. METHOD: The real-time PCR technique was applied to measure the expression levels of the selected lncRNAs (LINC01913 and LINC00671) and EMT-related mRNAs (MAMLs and MMP-13) in 83 tumor and adjacent normal tissues obtained from GC patients. RESULT: A significant reduction in LINC00671 expression was observed in 55.4% of tumor tissues, while elevated expression of LINC01913 (41%), MMP13 (56.6%), and MAML1 (44.6%) was detected, representing the proportion of samples with dysregulated expression relative to matched normal tissues. Dysregulation of these genes was significantly associated with various clinicopathological features (P&#x2009;<&#x2009;0.05), supporting a potential link between these lncRNAs and EMT processes in GC. CONCLUSION: The observed associations between LINC00671, LINC01913, and EMT-related genes suggest their potential as prognostic biomarkers for treatment response in GC patients.

Humans

Exploring the transcriptional cooperation between RUNX2 and its associated elncRNA RAIN.

Recent insights into the mechanisms controlling gene expression identified enhancer-associated long non-coding RNAs (elncRNAs) as master players of transcription in cancers. RUNX2, a mammalian RUNT-related transcription factor, is increasingly recognized in cancer biology for its role in supporting survival and progression also in thyroid cancer (TC). We recently identified, within the RUNX2 locus, a novel elncRNA that we named RAIN (RUNX2 associated intergenic lncRNA). We showed that RAIN and RUNX2 expression correlate in TC, both in vitro and in vivo, and that RAIN promotes RUNX2 expression by interacting with and affecting the activity of the RUNX2 P2 promoter through two distinct mechanisms. Here, we took forward these observations to explore the genome-wide transcriptional function of RAIN and its contribution to the RUNX2-dependent gene expression program in TC. By combining multiple omics data, we demonstrated that RAIN functionally cooperates with RUNX2 to the regulation of a subset of functionally related genes involved in promoting matrix remodeling, migration, and loss of differentiation. We showed that RAIN interacts with RUNX2 and its expression is required for the efficient recruitment of this TF to its target regulatory regions. In addition, our data revealed that besides RUNX2, RAIN governs a hierarchically organized complex transcriptional program by controlling a core of cancer-associated TFs that, in turn, orchestrate the expression of downstream genes. This evidence indicates that the functional cooperation observed between RAIN and RUNX2 can be a diffuse work mechanism for this elncRNA.

Core Binding Factor Alpha 1 Subunit

Future of rAAV Gene Therapy: Platform for RNAi, Gene Editing, and Beyond.

The use of recombinant adeno-associated viruses (rAAVs) ushered in a new millennium of gene transfer for therapeutic treatment of a number of conditions, including congenital blindness, hemophilia, and spinal muscular atrophy. rAAV vectors have remarkable staying power from a therapeutic standpoint, withstanding several ebbs and flows. As new technologies such as clustered regularly interspaced short palindromic repeat genome editing emerge, it is now the delivery tool-the AAV vector-that is the stalwart. The long-standing safety of this vector in a multitude of clinical settings makes rAAV a selling point in the advancement of approaches for gene replacement, gene knockdown, gene editing, and genome modification/engineering. The research community is building on these advances to develop more tailored delivery approaches and to tweak the genome in new and unique ways. Intertwining these approaches with newly engineered rAAV vectors is greatly expanding the available tools to manipulate gene expression with a therapeutic intent.

Dependovirus

Comparative transcriptome analysis of Qinchuan and Wagyu cattle reveals lnc11599 as a negative regulator of intramuscular fat deposition.

BACKGROUND: Intramuscular fat (IMF) content is a critical factor determining beef quality, influenced by various factors including breed and age. However, the regulatory role of long non-coding RNAs (lncRNAs) in IMF deposition remains unclear. METHODS: This study investigated IMF deposition in the longissimus dorsi muscle of one- and two-year-old Qinchuan and Wagyu cattle through histological examination and fat content measurement. Based on transcriptome sequencing data of intramuscular fat tissue, differential expression analysis and weighted gene co-expression network analysis (WGCNA) were performed to identify lncRNAs associated with IMF deposition. The effects of a key candidate lncRNA on the adipogenic differentiation of cattle intramuscular preadipocytes were further examined. RESULTS: Results showed that Wagyu cattle exhibited stronger IMF deposition capacity than Qinchuan cattle across all age groups, with IMF content increasing with age in both breeds. We identified 7,910 lncRNAs from intramuscular fat tissue transcriptome data, including 6,455 novel lncRNAs. Through integrated differential expression analysis and WGCNA, 88 lncRNAs closely associated with IMF deposition were screened from two-year-old Qinchuan and Wagyu cattle. Notably, lnc11599 was significantly upregulated in Qinchuan cattle intramuscular fat tissue, but its expression decreased during intramuscular preadipocyte differentiation. Functional experiments demonstrated that lnc11599 knockdown enhanced adipogenic differentiation capacity, manifested as a highly significant increase in lipid accumulation, upregulation of key adipogenic genes at the mRNA level, together with increases in total fatty acid content and unsaturated fatty acid proportion. CONCLUSIONS: This study established the lncRNA expression profiles in intramuscular fat tissue of Qinchuan and Wagyu cattle across different developmental stages, and demonstrated that lnc11599 acts as a negative regulator of intramuscular fat deposition. These findings provide new directions for elucidating the mechanisms of cattle IMF deposition and offer potential targets for genetic improvement of beef quality.

Animals

The regulatory role of non-coding RNAs in taxane resistance of breast cancer.

Breast cancer remains a major health concern among women, characterized by a high risk and substantial mortality. Chemotherapy is widely employed as a standard treatment modality to eliminate malignant cells and improve patient survival. Nevertheless, recurrence and chemoresistance arising from taxane treatment have emerged as key factors driving the high mortality rates in cancer patients. Non-coding RNAs (ncRNAs), encompassing microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), represent a key functional output of the human genome and, via intricate regulatory networks, influence nearly all facets of cancer biology, including the development of chemoresistance. Importantly, in taxane-resistant breast cancer cells, the identified miRNAs displayed bifunctional roles: some promoted resistance, whereas others enhanced sensitivity. This functional duality is also observed in lncRNAs, highlighting their context&#x2011;dependent regulatory roles. Additionally, ncRNAs are enriched in taxane-resistant cells-derived exosomes, where they play a crucial role in spreading taxane resistance and chemotherapy failure through genetic modulation of taxane&#x2011;sensitive cells. Notably, targeting ncRNAs via various therapeutic approaches, including herbal compounds and synthetic peptides, has shown hopeful findings in reversing taxane resistance in breast cancer, highlighting a promising avenue for the management of taxane resistance in breast cancer.

Breast cancer

RNA splicing and cardiovascular disease: a guide for cardiologists.

Alternative splicing (AS) is a fundamental RNA processing mechanism, which generates different RNA transcripts and consequently different protein isoforms from a single gene. This increases the diversity of proteins within an organism and can fine-tune biological processes. This review examines how cardiac-enriched RNA-binding proteins establish heart-specific splicing programs governing aspects of cardiac development, function, and disease. Developmentally, coordinated sarcomeric isoform switches underpin the foetal-to-adult transition and further isoform rewiring in ion channel and kinase genes determine electrophysiology and excitation-contraction coupling. AS contributes to the pathogenesis of several cardiomyopathies and emerging datasets suggest that pathological hypertrophy engages distinct splicing signatures compared with physiological hypertrophy. This review summarizes diagnostic and prognostic opportunities arising from bulk, long-read, and single-cell/nucleus transcriptomics, which resolve cell type-specific isoforms and disease-associated switches. Circulating RNA biomarkers (including splice ratios and circularRNAs) may signify myocardial remodelling and arrhythmic risk. Integrative approaches that link AS with proteomics and genomics improve variant interpretation, reveal previously unannotated protein isoforms, and enable tracking of disease progression and therapy response. Finally, an outline of therapeutic strategies to modulate AS in cardiovascular disease (CVD), including antisense oligonucleotides, small molecules, and genome-editing modalities (CRISPR, base, and prime editing), is provided. The major challenges that remain before splice-targeting therapeutics can be targeted to treat cardiovascular disease are highlighted. Lessons from neuromuscular indications establish clinical feasibility of splicing correction and motivate translation to cardiology. Together, mechanistic insight, biomarker development, and therapeutic innovation position RNA splicing as a tractable axis for precision cardiovascular medicine.

Humans

Targeting ncRNA control networks with engineered exosomes to overcome therapy resistance in thyroid cancer.

Papillary thyroid cancer (PTC) is the most prevalent endocrine malignancy, accounting for over 90% of thyroid cancers. While differentiated thyroid cancers (DTCs) typically have favorable outcomes, a significant subset progresses to radioactive iodine-refractory (RAIR) disease, characterized by impaired iodine uptake and a 10-year survival rate below 10%. Genetic alterations and dysregulated signaling pathways underlie this transition. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), circular RNAs (circRNAs), and long non-coding RNAs (lncRNAs), play critical regulatory roles in tumor biology and may be transported via exosomes, facilitating intercellular communication and contributing to RAIR-PTC. This systematic review, conducted according to PRISMA 2020 guidelines, evaluated the role of exosomal ncRNAs in RAIR-PTC. A comprehensive search of PubMed, PubMed Central, and Google Scholar identified studies published within the past 15 years in English. Following stringent quality appraisal, studies with a non-bias score above 40% were included. Of 961 identified publications, 96 high-quality studies met inclusion criteria. Evidence indicates that therapy resistance in RAIR-PTC is driven by convergent ncRNA regulatory networks that suppress sodium-iodide symporter (NIS) expression and activate oncogenic pathways, most notably MAPK, PI3K/AKT/mTOR, and Wnt/&#x3b2;-catenin signaling. Multiple ncRNAs converge on key regulatory nodes, forming redundant circuits that sustain dedifferentiation, metabolic adaptation, and impaired iodide transport. Several consistently dysregulated ncRNAs directly or indirectly regulate NIS expression and trafficking, highlighting actionable targets. Exosomes emerge as biologically compatible, programmable delivery vehicles capable of transporting therapeutic ncRNA payloads independent of endogenous packaging mechanisms. These findings support a precision therapeutic paradigm in which engineered exosomes reprogram ncRNA networks to restore iodine-handling pathways and overcome therapy resistance in RAIR-PTC.

Humans

Genome-wide association study reveals two novel genetic loci associated with chronic lung allograft dysfunction.

BACKGROUND: Chronic lung allograft dysfunction (CLAD) leads to declining respiratory function and high mortality, representing the main barrier to long-term survival in lung transplantation (LT). We performed the first genome-wide association study (GWAS) investigating donor's and recipient's genetic factors associated with CLAD. METHOD: We genotyped 392 donor-recipient pairs from the multicentric Cohort in Lung Transplantation. We tested 4.5 million SNPs for association with CLAD using multivariable logistic regression models corrected for age, sex, initial disease and genetic ancestry. Three levels of explanatory variables were separately considered to conduct GWAS: donors-only, recipients-only, and donor-recipient mismatches. We also ran HLA-centric analyses using the same models. RESULTS: Our analysis confirmed the deleterious impact of HLA allelic and epitopic mismatches on CLAD risk, mostly driven by class I HLA (p=0.004). No significant associations with CLAD were found for donors' genotypes or donor-recipient non-HLA mismatches. We highlighted two independent recipient's loci associated with CLAD, including one protective signal (0.39 in CLAD vs 0.66 in non-CLAD recipients, p-value=5.05&#xd7;10-7, q-value=0.017, OR=0.35) encompassing the PLXDC2 gene, and one risk signal (0.66 in CLAD vs 0.38 in non-CLAD recipients, p-value=9.86&#xd7;10-7, q-value=0.017, OR=2.83) encompassing the ZNF518A/BLNK genes. These non-coding SNPs are putative regulatory variants of gene expression. Importantly, our single-cell RNA-sequencing showed a down-regulation of PLXDC2 in fibroblasts and lung epithelium in CLAD vs healthy controls. CONCLUSION: This first LT GWAS revealed two candidate loci from the recipient's genome, both biologically relevant for CLAD pathogenesis. Our study calls for larger LT genomic initiatives to increase power for signal discovery.

Humans