Molecular Genetics and Genomics最新文献

{"title":"HuR modulates disease-relevant alternative splicing of MAPT and other Alzheimer's disease-related genes.","authors":"Yaqiong Yu, Shengyan Liu, Chao Ma, Mingliang Tan, Lingxia Min, Tao Jiang, Deng Xiao","doi":"10.1007/s00438-026-02527-8","DOIUrl":"https://doi.org/10.1007/s00438-026-02527-8","url":null,"abstract":"<p><p>Alternative splicing of MAPT exon 10 generates 4R- and 3R-Tau isoforms, and its dysregulation is associated with tauopathies including Alzheimer's disease (AD), for which effective treatments remain lacking. Here, we identify HuR as a novel repressor of MAPT exon 10 alternative splicing. Mechanistically, the RRM1 domain of HuR is critical for mediating its splicing inhibitory effect. HuR binds to the U-rich region downstream of intron 9 in MAPT together with FUBP1, KHSRP, hnRNPD, hnRNPAB, hnRNPDL, and TIAL1. The expression of HuR shows a negative association with that of FUBP1, KHSRP, hnRNPD, and TIAL1. Finally, we demonstrate that HuR regulates the expression and alternative splicing of genes involved in autophagy and apoptosis, pathways dysregulated in AD. Collectively, these findings establish HuR as a regulator of AD-relevant transcriptomic networks and provide a mechanistic basis for exploring HuR-targeted strategies in AD.</p>","PeriodicalId":18816,"journal":{"name":"Molecular Genetics and Genomics","volume":"301 1","pages":""},"PeriodicalIF":2.2,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149183109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"USP11 inhibits cuproptosis in non-small cell lung cancer by deubiquitinating IGF2BP2 to enhance the stability of m6A-modified ATOX1 mRNA.","authors":"Lin Wang, Jiansheng Li, Hongxia Li","doi":"10.1007/s00438-026-02531-y","DOIUrl":"https://doi.org/10.1007/s00438-026-02531-y","url":null,"abstract":"<p><p>Inducing cuproptosis is considered a novel strategy to impede non-small cell lung cancer (NSCLC) progression. ATOX1 suppressed cuproptosis by chelating free copper ions. This study seeks to elucidate the pathways that regulate ATOX1 upstream and thereby pinpoint molecular targets for activating cuproptosis in NSCLC. Cuproptosis was induced with ES-Cu. Malignant phenotypes were assessed using CCK-8, clonogenic, and Transwell assays. RNA immunoprecipitation, RNA pull-down, and actinomycin D chase were used to examine IGF2BP2-ATOX1 mRNA interaction and mRNA stability. Protein-protein interactions and ubiquitination were examined by co-immunoprecipitation. The co-localization of USP11 and IGF2BP2 was visualized by immunofluorescence. IGF2BP2 protein stability was assessed following cycloheximide treatment. Copper content was quantified using a commercial kit. Gene and protein levels were evaluated by RT-qPCR and Western blot. RNA-binding domain mutant rescue experiments were conducted to determine the functional requirement of IGF2BP2 KH domains. A subcutaneous xenograft model was established to validate the regulatory axis in vivo. ATOX1 suppressed cuproptosis to support NSCLC proliferation. IGF2BP2 bound to the CDS of ATOX1 mRNA via the m6A site at position 261, thereby enhancing ATOX1 mRNA stability. The KH3-4 domains of IGF2BP2 were indispensable for this regulation. Upregulation of ATOX1 by IGF2BP2 inhibited cuproptosis and consequently drove NSCLC proliferation. USP11 maintained IGF2BP2 protein stability via deubiquitination, leading to suppression of cuproptosis and promotion of NSCLC progression through the IGF2BP2/ATOX1 axis in vitro. In vivo, the USP11-IGF2BP2-ATOX1 axis might promote NSCLC tumor growth by suppressing cuproptosis. USP11‑dependent deubiquitination stabilized IGF2BP2, which subsequently increased ATOX1 mRNA stability in an m6A‑dependent manner. Elevated ATOX1 expression inhibited cuproptosis and thereby accelerated NSCLC progression.</p>","PeriodicalId":18816,"journal":{"name":"Molecular Genetics and Genomics","volume":"301 1","pages":""},"PeriodicalIF":2.2,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149183056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional characterization of genetic variants associated with rare inherited renal disorders in the Sri Lankan population.","authors":"K M Fathima Rizna, Nafeesa Noordeen, W M Manoj S Bandara, Hasani Hewavitharana, Bhagya Hendalage, Nilaksha Neththikumara, Dineshani Hettiarachchi, Vajira H W Dissanayake","doi":"10.1007/s00438-026-02524-x","DOIUrl":"10.1007/s00438-026-02524-x","url":null,"abstract":"<p><p>Rare inherited renal disorders (RIRD) are genetically heterogeneous conditions that contribute substantially to morbidity and mortality, particularly among pediatric and young adult populations. Although next-generation sequencing has improved diagnostic yield, functional interpretation of novel variants and variants of uncertain significance remains limited, especially in underrepresented populations such as Sri Lankans. This study aimed to functionally characterize genetic variants identified through whole-exome sequencing (WES) in Sri Lankan patients with clinically diagnosed RIRD. In RT-qPCR analysis, AVPR2 (Missense), DAAM2, OCRL, and CLCN5showed downregulation, while NPHS2 and COL4A5 showed upregulation in patient samples. Notably, DAAM2 expression was strongly downregulated, indicating potential functional relevance of its associated VUS. In silico protein modeling predicted significant structural disruption in several truncating variants, including COL4A5, OCRL, and AVPR2(frameshift), suggesting loss of functional domains or premature termination of protein synthesis. A missense variant in AVPR2 was predicted to affect the transmembrane region. RT-qPCR analysis supported the findings of protein modeling, demonstrating absent or reduced gene expression consistent with the protein modeling. Integrating protein modeling with gene expression analysis provides valuable functional insights into rare inherited renal disease-associated variants. This study supports the potential reclassification of selected variants and contributes to population-specific functional data, improving genetic interpretation and diagnostic precision for RIRD in Sri Lanka.</p>","PeriodicalId":18816,"journal":{"name":"Molecular Genetics and Genomics","volume":"301 1","pages":""},"PeriodicalIF":2.2,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112180","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CRP-albumin-lymphocyte index and multisystem diseases: a phenome-wide Mendelian randomization study.","authors":"Ben Niu, Ming-Hui Xia, Jia-Xin Wu, Pei He, Lin Bo, Hai-Ying Wu, Shu-Feng Lei, Fei-Yan Deng","doi":"10.1007/s00438-026-02513-0","DOIUrl":"10.1007/s00438-026-02513-0","url":null,"abstract":"<p><p>The C-reactive protein-albumin-lymphocyte (CALLY) index is a composite biomarker integrating inflammation, nutrition, and immune function, but its causal relationships with a broad spectrum of human diseases and potential utility for public health risk prediction remain unclear. We conducted a population-based genetic epidemiological study combining genome-wide association study (GWAS), phenome-wide association study (PheWAS), and two-sample Mendelian randomization (MR), using data from the UK Biobank (265,409 participants for GWAS; 113,747 participants for PheWAS) and FinnGen to construct genetic instruments for the CALLY index, perform PheWAS across 713 phenotypes, evaluate causal associations via two-sample MR, and conduct sensitivity analyses including linkage disequilibrium score regression and pleiotropy testing. GWAS identified 154 genomic loci significantly associated with the CALLY index; PheWAS detected 24 significant phenotype associations, with higher genetically predicted CALLY index linked to lower risks of Alzheimer's disease, Alzheimer's dementia, unspecified dementia, and lipid metabolism disorders. MR confirmed causal protective effects for these neurodegenerative outcomes while indicating a causal association with increased sleep disorder risk, and pleiotropic analyses highlighted shared biological pathways in lipid metabolism and inflammation. These findings demonstrate that the CALLY index is causally associated with neurodegenerative, metabolic, and sleep disorders, supporting its role as a promising integrated biomarker for disease risk stratification and public health applications.</p>","PeriodicalId":18816,"journal":{"name":"Molecular Genetics and Genomics","volume":"301 1","pages":""},"PeriodicalIF":2.2,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149075280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cannabidiol (CBD) differentially shapes systemic cytokines and transcriptomic profiles in the liver and spleen: insights from a male mouse model.","authors":"Jakub Żurowski, E Ocłoń, I Jasielczuk, T Szmatoła, K Mizera-Szpilka, E Semik-Gurgul, S Sawicki, Artur Gurgul","doi":"10.1007/s00438-026-02525-w","DOIUrl":"10.1007/s00438-026-02525-w","url":null,"abstract":"<p><p>Cannabidiol (CBD) is widely studied for its anti-inflammatory and immunomodulatory properties, yet its relationship with systemic cytokine responses and organ-level transcriptional changes remains incompletely defined. Here, we investigated the dose- and time-dependent effects of CBD on circulating pro-inflammatory cytokines and the transcriptomic profiles of the liver and spleen in male C57BL/6J mice. Animals received CBD intraperitoneally at 0.2, 10, or 20 mg/kg body weight for either 2 days (short-term, ST) or 28 days (long-term, LT), with vehicle-treated controls. Serum IL-1β, IL-6, and TNF-α were measured by ELISA, and RNA-Seq was performed on liver and spleen to characterize differential gene expression and enriched biological processes. CBD significantly reduced IL-1β and TNF-α after ST treatment across doses, whereas IL-6 decreased primarily during LT exposure, with the strongest reduction at day 14 and partial persistence to day 28 at higher doses. Transcriptomic responses were markedly organ- and regimen-dependent. The liver transcriptome exhibited pronounced, dose- and time-dependent remodeling, with the largest number of differentially expressed genes at 20 mg/kg in ST and broad changes across doses in LT. The gene enrichment analyses indicated modulation of mitochondrial and translational pathways after ST high-dose exposure, lipid and fatty acid metabolism during LT, as well as circadian-associated regulation at higher-dose LT treatment, with innate immune-associated signaling terms enriched at the highest dose. In contrast, the spleen displayed comparatively modest transcriptional changes, with limited differential expression in LT and a clearer response only after ST exposure to 20 mg/kg, where altered genes showed trends related to lipid-associated processes. Together, these findings demonstrate that CBD attenuates circulating pro-inflammatory cytokines while inducing strong, dose- and time-dependent hepatic transcriptional reprogramming and relatively limited splenic transcriptomic shifts. The integration of systemic and organ-specific data supports a model in which CBD acts as a systemic immunometabolic modulator rather than a simple immunosuppressant.</p>","PeriodicalId":18816,"journal":{"name":"Molecular Genetics and Genomics","volume":"301 1","pages":""},"PeriodicalIF":2.2,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13619664/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149075344","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Codon optimality predicts mRNA half-life but does not transfer to lncRNAs.","authors":"Hidenori Tani","doi":"10.1007/s00438-026-02520-1","DOIUrl":"10.1007/s00438-026-02520-1","url":null,"abstract":"<p><p>Codon optimality couples translation elongation to decay and is among the strongest reported sequence determinants of mRNA half-life. Long non-coding RNAs (lncRNAs) are largely untranslated. Is lncRNA stability sequence-encoded in the way mRNA stability is? We compared the classes on half-lives from the same assays, re-estimating the codon stabilization coefficient (CSC) inside each cross-validation fold to remove label leakage. Performance is the cross-validated coefficient of determination R² - 1 for perfect prediction, 0 for the training mean, negative for worse - and the Spearman rank correlation ρ between predicted and measured half-life. mRNA half-life was sequence-predictable (R² = 0.174, ρ = 0.44), and CSC alone (R² = 0.084) outperformed a six-member translation-independent set (R² = 0.008), an ordering that held in three further datasets, two assays and two species. lncRNA half-life was not: R² = -0.050 in same-assay HeLa lncRNAs (n = 364) and R² = +0.0007 from k-mer composition in the largest published lncRNA dataset (n = 33,285), where that study's own cross-validated ρ is 0.091. That value clears its permutation null: the classes differ in magnitude, not detectability. Pretrained genomic language models, one covering 99.6% of transcripts whole, left mRNAs at R² = 0.042 and lncRNAs at 0.0002-0.0036. Coding-potential strata change nothing; matching on length, GC and n with an identical feature set gives R² = 0.033 versus 0.0002. Signal injection puts the reliable detection limit near 0.5% of variance, above every lncRNA value obtained. mRNA-derived decay models should not be transferred to lncRNAs without re-validation.</p>","PeriodicalId":18816,"journal":{"name":"Molecular Genetics and Genomics","volume":"301 1","pages":""},"PeriodicalIF":2.2,"publicationDate":"2026-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149002221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neurexophilin 4 facilitates the malignant progression of kidney renal clear cell carcinoma by regulating PI3K/AKT-mediated glycolysis.","authors":"Xiaolei Lv, Haitao Gao, Dawei Cui, Jianxing Li, Xiujun Li, Yan Liu","doi":"10.1007/s00438-026-02483-3","DOIUrl":"10.1007/s00438-026-02483-3","url":null,"abstract":"<p><p>Clear cell renal cell carcinoma (ccRCC) is a major subtype of renal cell carcinoma and characterized by metabolic reprogramming, especially glycolysis. Neurexophilin 4 (NXPH4) is associated with malignancy of several cancers. However, its function in ccRCC remains unclear. In the current study, several online bioinformatics databases confirmed that NXPH4 was highly expressed in ccRCC tissues and was correlated with poor prognosis in patients with ccRCC. Notably, inhibition of NXPH4 suppressed cell viability, invasion and migration of ccRCC cells, and promoted cell apoptosis; while its overexpression produced the opposite effects. Further online database revealed a positive correlation between NXPH4 expression and glycolysis-related genes LDHA and HK2 in ccRCC tissues. Suppression of NXPH4 obviously decreased protein expression of LDHA and HK2 in ccRCC cells. Importantly, knockdown of NXPH4 attenuated glycolysis by inhibiting glucose uptake, lactate, ATP levels, extracellular acidification rate (ECAR) and increasing oxygen consumption rate (OCR); however, NXPH4 up-regulation promoted glycolysis. Intriguingly, the pro-tumor effects of NXPH4 were reversed by the glycolysis antagonist 2-DG. Additionally, NXPH4 elevation activated the PI3K/AKT pathway, while blocking this pathway significantly offset NXPH4-driven glycolysis, viability, invasion and migration. Collectively, NXPH4 may contribute to cancer cell growth and metastatic potential in ccRCC by activating the PI3K/AKT-evoked glycolysis, supporting it as a promising therapeutic target for ccRCC.</p>","PeriodicalId":18816,"journal":{"name":"Molecular Genetics and Genomics","volume":"301 1","pages":""},"PeriodicalIF":2.2,"publicationDate":"2026-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149008684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The phosphate specific transport system protein PhoU modulates persister cell formation of Klebsiella pneumoniae.","authors":"Yanxin Sun, Weihao Xu, Kexu Chen, Xinyu Hong, Xuhong Sun, Wenru Ma, Xin Wang, Qingmei Cao, Zhaoping Xue, Bingcun Zhou, Yuhui Zhang, Zhijun Liu, Zimai Cui, Dahui Wang, Zhouyan Dong, Yumei Zhang","doi":"10.1007/s00438-026-02509-w","DOIUrl":"10.1007/s00438-026-02509-w","url":null,"abstract":"<p><p>The indiscriminate use of antibiotics has exacerbated the clinical challenge posed by Klebsiella pneumoniae, with persisters often evading antibiotic treatment. To investigate the mechanisms underlying persister formation, we identified the phosphate transporter gene phoU as differentially expressed during persister emergence and recovery. Using CRISPR-Cas9 gene editing, we created a ∆phoU knockout strain in K. pneumoniae ATCC 700603, along with its complemented (CphoU) and various overexpression strains (OE phoU, OE metE, and OE phoA). While growth rates and antibiotic susceptibility remained unchanged in the ∆phoU strain, its capacity to form persisters under levofloxacin and tobramycin stress was significantly reduced. Metabolomic and transcriptomic analyses linked phoU deletion to downregulation of metE (involved in methionine synthesis) and phoA (encoding alkaline phosphatase). ∆phoU also exhibited impaired biofilm formation and reduced extracellular polymeric substance (EPS) production compared to WT, CphoU, and the OE metE and OE phoA overexpression strains. Complementation of metE or phoA partially restored both biofilm formation and persister levels. Importantly, the reduction in persisters is primarily attributed to metabolic defects in planktonic cells-specifically, impaired methionine synthesis and stress response-rather than to reduced biofilm mass, which is considered a parallel phenotype. We conclude that PhoU promotes K. pneumoniae persistence by transcriptionally upregulating metE and phoA, thereby supporting the stress response capacity of planktonic cells. This study elucidates a novel pathway for persister formation and identifies PhoU and its downstream targets as potential therapeutic vulnerabilities.</p>","PeriodicalId":18816,"journal":{"name":"Molecular Genetics and Genomics","volume":"301 1","pages":""},"PeriodicalIF":2.2,"publicationDate":"2026-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149002281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retraction Note: Buparlisib induces eukaryotic elongation factor-2 expression to cause treatment failure for lung cancer cells.","authors":"DanPing Wang, ChenLi Su, Xiao Zhang, Wei Mao, XiaoQiang Dai, Li Xu, XiaoMin Si","doi":"10.1007/s00438-026-02522-z","DOIUrl":"10.1007/s00438-026-02522-z","url":null,"abstract":"","PeriodicalId":18816,"journal":{"name":"Molecular Genetics and Genomics","volume":"301 1","pages":""},"PeriodicalIF":2.2,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149002229","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From scissors to editors: how the evolution of precision is redefining therapeutic genome editing.","authors":"Mohadese Rahbari, Reyhane Lohrasbi, Amir Amiri-Yekta","doi":"10.1007/s00438-026-02467-3","DOIUrl":"10.1007/s00438-026-02467-3","url":null,"abstract":"<p><p>Since its introduction as a genome-editing tool, CRISPR-based technology has undergone rapid refinement, with precision emerging as a central focus of development. Early CRISPR-Cas9 systems demonstrated unprecedented ease and efficiency in targeting specific DNA sequences, but concerns over off-target effects and variable editing outcomes limited their broader application. This review outlines the progression of CRISPR from its discovery in prokaryotes to its application as a versatile tool in precision medicine, where it supports targeted therapies for genetic disorders in various ways. Although technical challenges, including off-target editing and delivery inefficiencies, persist alongside ethical considerations of accessibility and long-term consequences, CRISPR's ongoing refinements and innovations reflect a clear trajectory toward greater specificity, safety, and predictability, positioning CRISPR as an increasingly precise platform for both fundamental research and therapeutic use.</p>","PeriodicalId":18816,"journal":{"name":"Molecular Genetics and Genomics","volume":"301 1","pages":""},"PeriodicalIF":2.2,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148983190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}