Pub Date : 2025-12-02DOI: 10.1016/j.gene.2025.149931
Jingzhi Chen , Xingmi Chen , Ying Liu , Chunming Lyu , Ming Xu , Yang Yang
Background
In metabolic dysfunction-associated fatty liver disease (MAFLD) research, reference genes for qPCR are crucial but often unvalidated.
Methods
RNA-seq was performed in control and free fatty acid (FFA) treated AML12 cells, and the candidates for reference gene were selected by previous literatures and filtered by dual-index ranking via normalization of coefficient variation and Log2FoldChange in the RNA-seq library. qPCR data was further analyzed via NormFinder, BestKeeper, geNorm, ΔCt and RefFinder to assess reference gene expression stability.
Results
FFA treated cells showed a significantly increased lipid droplet accumulation. RNA-seq dual-index ranking and RefFinder identified that Ywhaz was the most stable reference gene.
Conclusion
Our finding revealed that Ywhaz is the most stable reference gene for qPCR in the AML12 cell model of FFA-induced MAFLD, and provided a reliable procedure for screening reference genes.
{"title":"Reference genes for quantitative real-time polymerase chain reaction in in vitro non-alcoholic fatty liver disease","authors":"Jingzhi Chen , Xingmi Chen , Ying Liu , Chunming Lyu , Ming Xu , Yang Yang","doi":"10.1016/j.gene.2025.149931","DOIUrl":"10.1016/j.gene.2025.149931","url":null,"abstract":"<div><h3>Background</h3><div>In metabolic dysfunction-associated fatty liver disease (MAFLD) research, reference genes for qPCR are crucial but often unvalidated.</div></div><div><h3>Methods</h3><div>RNA-seq was performed in control and free fatty acid (FFA) treated AML12 cells, and the candidates for reference gene were selected by previous literatures and filtered by dual-index ranking via normalization of coefficient variation and Log<sub>2</sub>FoldChange in the RNA-seq library. qPCR data was further analyzed via NormFinder, BestKeeper, geNorm, ΔCt and RefFinder to assess reference gene expression stability.</div></div><div><h3>Results</h3><div>FFA treated cells showed a significantly increased lipid droplet accumulation. RNA-seq dual-index ranking and RefFinder identified that <em>Ywhaz</em> was the most stable reference gene.</div></div><div><h3>Conclusion</h3><div>Our finding revealed that <em>Ywhaz</em> is the most stable reference gene for qPCR in the AML12 cell model of FFA-induced MAFLD, and provided a reliable procedure for screening reference genes.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"979 ","pages":"Article 149931"},"PeriodicalIF":2.4,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145667852","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}
Pub Date : 2025-11-29DOI: 10.1016/j.gene.2025.149930
Huiqin Yang, Xihui Zhou
Background
PURA syndrome is a rare genetic disorder characterized by obvious hypotonia, feeding difficulties, apnea, and drowsiness, which is caused by variants in the Purine Rich Element Binding Protein A (PURA) on chromosome 5q31.2-q31.3, and is inherited in an autosomal dominant manner. This condition presents challenges for early diagnosis and effective treatment. This study investigates its pathogenic mechanisms and potential therapeutic strategies.
Methods
Peripheral blood samples were collected from a Chinese newborn with severe hypotonia and his parents. Whole-exome sequencing (WES) and Sanger validation identified a novel PURA variant, which had not been previously reported. To explore the potential involvement of nonsense-mediated mRNA decay (NMD) in PURA syndrome, wild-type (WT) and variant (Var) PURA expression vectors were constructed and transiently transfected into 293 T cells via liposomal transfection. Real-time quantitative polymerase chain reaction (PCR) and Western blotting were performed to analyze the PURA expression. The levels of PURA mRNA and protein were assessed following treatment with the NMD inhibitor cycloheximide (CHX) and the small interfering RNA targeting Up-frameshift protein 1 (siRNA-UPF1), a key NMD factor.
Results
The WES identified a novel heterozygous frameshift variant in exon 1 of PURA (NM_005859.5): c.632_651dup; p.(Leu218Trpfs*14), which introduces a premature termination codon (PTC). However, no such variant was detected in his parents. Functional validation assays revealed that the variant construct expressed significantly lower levels of PURA mRNA and protein compared to the WT. CHX treatment and siRNA-UPF1 transfection significantly increased the mRNA and protein expression levels of PURA in the variant construct.
Conclusion
The novel PURA variant, c.632_651dup; p.(Leu218Trpfs*14), is a pathogenic heterozygous frameshift. The NMD pathway is involved in the degradation of its aberrant transcript. Our research expands the genotypic spectrum of pathogenic PURA variants, and offers a new perspective for potential therapeutic intervention.
{"title":"A novel frameshift variant in PURA syndrome: role of NMD pathway in disease mechanism","authors":"Huiqin Yang, Xihui Zhou","doi":"10.1016/j.gene.2025.149930","DOIUrl":"10.1016/j.gene.2025.149930","url":null,"abstract":"<div><h3>Background</h3><div>PURA syndrome is a rare genetic disorder characterized by obvious hypotonia, feeding difficulties, apnea, and drowsiness, which is caused by variants in the <em>Purine Rich Element Binding Protein A (PURA)</em> on chromosome 5q31.2-q31.3, and is inherited in an autosomal dominant manner. This condition presents challenges for early diagnosis and effective treatment. This study investigates its pathogenic mechanisms and potential therapeutic strategies.</div></div><div><h3>Methods</h3><div>Peripheral blood samples were collected from a Chinese newborn with severe hypotonia and his parents. Whole-exome sequencing (WES) and Sanger validation identified a novel <em>PURA</em> variant, which had not been previously reported. To explore the potential involvement of nonsense-mediated mRNA decay (NMD) in PURA syndrome, wild-type (WT) and variant (Var) <em>PURA</em> expression vectors were constructed and transiently transfected into 293 T cells via liposomal transfection. Real-time quantitative polymerase chain reaction (PCR) and Western blotting were performed to analyze the <em>PURA</em> expression. The levels of <em>PURA</em> mRNA and protein were assessed following treatment with the NMD inhibitor cycloheximide (CHX) and the small interfering RNA targeting Up-frameshift protein 1 (siRNA-UPF1), a key NMD factor.</div></div><div><h3>Results</h3><div>The WES identified a novel heterozygous frameshift variant in exon 1 of PURA (NM_005859.5): c.632_651dup; p.(Leu218Trpfs*14), which introduces a premature termination codon (PTC). However, no such variant was detected in his parents. Functional validation assays revealed that the variant construct expressed significantly lower levels of <em>PURA</em> mRNA and protein compared to the WT. CHX treatment and siRNA-UPF1 transfection significantly increased the mRNA and protein expression levels of <em>PURA</em> in the variant construct.</div></div><div><h3>Conclusion</h3><div>The novel PURA variant, c.632_651dup; p.(Leu218Trpfs*14), is a pathogenic heterozygous frameshift. The NMD pathway is involved in the degradation of its aberrant transcript. Our research expands the genotypic spectrum of pathogenic <em>PURA</em> variants, and offers a new perspective for potential therapeutic intervention.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"984 ","pages":"Article 149930"},"PeriodicalIF":2.4,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145648071","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}
Pub Date : 2025-11-29DOI: 10.1016/j.gene.2025.149929
Si-han Liu , Xiao-yan Kong , Miao Li , Shu-mei Wang
Background
Pediatric brain tumors (PBTs) are the leading type of solid tumors in children, profoundly affecting both survival rates and quality of life. Methotrexate (MTX) is an essential chemotherapy drug for treating these tumors; however, its efficacy and toxicity vary among patients due to genetic factors.
Objective
This study examined the impact of the intronic rs3780130 polymorphism in the gamma-glutamyl hydrolase (GGH) gene on MTX concentrations and related toxicities in patients with PBTs.
Methods
The GGH rs3780130 T > A polymorphism was genotyped using the Sequenom MassARRAY iPLEX platform in a cohort of 73 PBT patients.
Results
We found that children with the AA genotype had significantly higher MTX concentrations compared to those with TT and TA genotypes (P < 0.05). Additionally, the AA genotype was significantly associated with a higher incidence of hepatotoxicity relative to the TT genotype (P < 0.05). It showed a significantly lower occurrence of gastrointestinal toxicities when compared to the TA genotype (P < 0.05). Bioinformatics analysis revealed that the rs3780130 polymorphism had a significant effect on GGH expression across various tissues, suggesting a potential mechanism by which this variant modulated MTX metabolism.
Conclusion
Our findings highlight the importance of GGH polymorphisms in personalizing MTX therapy for PBT patients and emphasize the necessity for further research to explore the clinical implications of GGH genotypes in larger cohorts, ultimately aiming for more precise therapeutic strategies.
背景：儿童脑肿瘤（PBTs）是儿童实体肿瘤的主要类型，深刻影响着儿童的生存率和生活质量。甲氨蝶呤（MTX）是治疗这些肿瘤的重要化疗药物；然而，由于遗传因素，其疗效和毒性因患者而异。目的：研究γ -谷氨酰水解酶（GGH）基因rs3780130内含子多态性对pbt患者MTX浓度及相关毒性的影响。方法：使用Sequenom MassARRAY iPLEX平台对73例PBT患者的GGH rs3780130 T > A多态性进行基因分型。结果：我们发现AA基因型儿童的MTX浓度明显高于TT和TA基因型儿童（P ）。结论：我们的研究结果强调了GGH多态性对PBT患者个性化MTX治疗的重要性，并强调了进一步研究的必要性，以在更大的队列中探索GGH基因型的临床意义，最终旨在制定更精确的治疗策略。
{"title":"GGH intronic variant rs3780130 is associated with methotrexate levels in children with brain tumors","authors":"Si-han Liu , Xiao-yan Kong , Miao Li , Shu-mei Wang","doi":"10.1016/j.gene.2025.149929","DOIUrl":"10.1016/j.gene.2025.149929","url":null,"abstract":"<div><h3>Background</h3><div>Pediatric brain tumors (PBTs) are the leading type of solid tumors in children, profoundly affecting both survival rates and quality of life. Methotrexate (MTX) is an essential chemotherapy drug for treating these tumors; however, its efficacy and toxicity vary among patients due to genetic factors.</div></div><div><h3>Objective</h3><div>This study examined the impact of the intronic rs3780130 polymorphism in the gamma-glutamyl hydrolase (<em>GGH</em>) gene on MTX concentrations and related toxicities in patients with PBTs.</div></div><div><h3>Methods</h3><div>The <em>GGH</em> rs3780130 T > A polymorphism was genotyped using the Sequenom MassARRAY iPLEX platform in a cohort of 73 PBT patients.</div></div><div><h3>Results</h3><div>We found that children with the AA genotype had significantly higher MTX concentrations compared to those with TT and TA genotypes (<em>P</em> < 0.05). Additionally, the AA genotype was significantly associated with a higher incidence of hepatotoxicity relative to the TT genotype (<em>P</em> < 0.05). It showed a significantly lower occurrence of gastrointestinal toxicities when compared to the TA genotype (<em>P</em> < 0.05). Bioinformatics analysis revealed that the rs3780130 polymorphism had a significant effect on <em>GGH</em> expression across various tissues, suggesting a potential mechanism by which this variant modulated MTX metabolism.</div></div><div><h3>Conclusion</h3><div>Our findings highlight the importance of <em>GGH</em> polymorphisms in personalizing MTX therapy for PBT patients and emphasize the necessity for further research to explore the clinical implications of <em>GGH</em> genotypes in larger cohorts, ultimately aiming for more precise therapeutic strategies.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"979 ","pages":"Article 149929"},"PeriodicalIF":2.4,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145653732","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}
Pub Date : 2025-11-28DOI: 10.1016/j.gene.2025.149928
T. Nagarajan , N. Arulmuthu Kumaran
Rescuing stalled ribosomes from the truncated mRNA is identified as a crucial process for the survival of a bacterial cell. A small RNA named tmRNA (transfer messenger RNA), and protein SmpB (Small protein B), together constitute a ribosome rescue apparatus which is ubiquitous among most of the eubacteria. tmRNA mediated ribosome rescue process (also called trans-translation) has been found to be the major pathway of clearance of stalled ribosome complexes. In the process, tmRNA-SmpB complex recycles stalled ribosomes by making them undergo normal translation and termination. Apart from rescuing stalled ribosomes, trans-translation modulates other cellular pathways (such as cell cycle, oxidative stress, nutritional stress, DNA damage response and so on) by regulating the intracellular level of various proteins. It becomes more and more obvious that the function of trans-translation apparatus is diverse and plays a role in bacterial pathogenesis also. This review will focus on the key findings on the involvement of tmRNA and its partner SmpB in regulation of pathogenesis and virulence in different pathogenic bacteria.
从截断的mRNA中挽救停滞的核糖体被认为是细菌细胞存活的关键过程。一种名为tmRNA （transfer messenger RNA）的小RNA和蛋白质SmpB （small protein B）共同构成了一种核糖体拯救装置，在大多数真细菌和古细菌中普遍存在。tmRNA介导的核糖体拯救过程（也称为反翻译）被发现是清除停滞核糖体复合物的主要途径。在这个过程中，tmRNA-SmpB复合体循环通过使核糖体进行正常的翻译和终止而使核糖体停滞。除了挽救停滞的核糖体外，反翻译还通过调节细胞内各种蛋白质的水平来调节其他细胞通路（如细胞周期、氧化应激、营养应激、DNA损伤反应等）。反翻译体的功能多样性越来越明显，在细菌的发病机制中也发挥着重要作用。本文将重点介绍tmRNA及其伴合体SmpB在不同致病菌的发病机制和毒力调控中的重要发现。
{"title":"Reassessing the tmRNA-SmpB complex as a virulence determinant","authors":"T. Nagarajan , N. Arulmuthu Kumaran","doi":"10.1016/j.gene.2025.149928","DOIUrl":"10.1016/j.gene.2025.149928","url":null,"abstract":"<div><div>Rescuing stalled ribosomes from the truncated mRNA is identified as a crucial process for the survival of a bacterial cell. A small RNA named tmRNA (transfer messenger RNA), and protein SmpB (Small protein B), together constitute a ribosome rescue apparatus which is ubiquitous among most of the eubacteria. tmRNA mediated ribosome rescue process (also called <em>trans</em>-translation) has been found to be the major pathway of clearance of stalled ribosome complexes. In the process, tmRNA-SmpB complex recycles stalled ribosomes by making them undergo normal translation and termination. Apart from rescuing stalled ribosomes, <em>trans</em>-translation modulates other cellular pathways (such as cell cycle, oxidative stress, nutritional stress, DNA damage response and so on) by regulating the intracellular level of various proteins. It becomes more and more obvious that the function of <em>trans</em>-translation apparatus is diverse and plays a role in bacterial pathogenesis also. This review will focus on the key findings on the involvement of tmRNA and its partner SmpB in regulation of pathogenesis and virulence in different pathogenic bacteria.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"979 ","pages":"Article 149928"},"PeriodicalIF":2.4,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145648023","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}
Ascorbate peroxidase (APX) enzymes are pivotal in scavenging reactive oxygen species (ROS) and maintaining redox homeostasis in plants, a function critical for survival under abiotic stress conditions. To investigate this key enzyme system in the rubber-producing dandelion Taraxacum kok-saghyz (Tk)—an emerging model for sustainable rubber production—we conducted a genome-wide analysis of its APX genes. We identified seven TkAPX genes, whose predicted subcellular localizations include the cytoplasm, plasma membrane, and chloroplasts. Promoter analysis revealed an abundance of stress-responsive motifs, supporting their potential role in stress adaptation. By integrating time-course qPCR of the TkAPX family under heat stress with transcriptome-wide expression profiling across tissues, we identified TkAPX250a as a pivotal candidate. This gene showed a remarkable ∼ 20-fold increase in transcript levels in subsequent transgenic lines compared to wild-type controls, confirming highly efficient transgene expression without silencing. Under thermal stress, these transgenic lines exhibited reduced ROS accumulation and membrane lipid peroxidation while maintaining higher chlorophyll content and biomass, demonstrating that TkAPX250a coordinately enhances thermotolerance and photosynthetic stability. Mechanistically, TkAPX250a overexpression not only enhanced APX activity and lowered H2O2 accumulation but also synergistically upregulated the activities of superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD). Time-resolved assays under heat stress further delineated a stratified antioxidant hierarchy within this coordinated response, with SOD and CAT acting as core responders. These findings establish TkAPX250a as a central genetic regulator in abiotic stress adaptation and provide a molecular basis for breeding stressresilient rubber crops, addressing a critical need in agriculture under changing climate conditions.
{"title":"Identification of ascorbate peroxidase family genes reveals expression of TkAPX250a confers heat stress tolerance in Taraxacum kok-saghyz","authors":"Shiqi Long, Boxuan Yuan, Minmin He, Guoen Ao, Baoqiang Wang, Xuchu Wang","doi":"10.1016/j.gene.2025.149918","DOIUrl":"10.1016/j.gene.2025.149918","url":null,"abstract":"<div><div>Ascorbate peroxidase (APX) enzymes are pivotal in scavenging reactive oxygen species (ROS) and maintaining redox homeostasis in plants, a function critical for survival under abiotic stress conditions. To investigate this key enzyme system in the rubber-producing dandelion <em>Taraxacum kok-saghyz</em> (Tk)—an emerging model for sustainable rubber production—we conducted a genome-wide analysis of its APX genes. We identified seven TkAPX genes, whose predicted subcellular localizations include the cytoplasm, plasma membrane, and chloroplasts. Promoter analysis revealed an abundance of stress-responsive motifs, supporting their potential role in stress adaptation. By integrating time-course qPCR of the TkAPX family under heat stress with transcriptome-wide expression profiling across tissues, we identified <em>TkAPX250a</em> as a pivotal candidate. This gene showed a remarkable ∼ 20-fold increase in transcript levels in subsequent transgenic lines compared to wild-type controls, confirming highly efficient transgene expression without silencing. Under thermal stress, these transgenic lines exhibited reduced ROS accumulation and membrane lipid peroxidation while maintaining higher chlorophyll content and biomass, demonstrating that TkAPX250a coordinately enhances thermotolerance and photosynthetic stability. Mechanistically, <em>TkAPX250a</em> overexpression not only enhanced APX activity and lowered H<sub>2</sub>O<sub>2</sub> accumulation but also synergistically upregulated the activities of superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD). Time-resolved assays under heat stress further delineated a stratified antioxidant hierarchy within this coordinated response, with SOD and CAT acting as core responders. These findings establish TkAPX250a as a central genetic regulator in abiotic stress adaptation and provide a molecular basis for breeding stressresilient rubber crops, addressing a critical need in agriculture under changing climate conditions.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"980 ","pages":"Article 149918"},"PeriodicalIF":2.4,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145632207","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}
Pub Date : 2025-11-25DOI: 10.1016/j.gene.2025.149919
Carlotta Frascolla , Riccardo Mastroianni , Giuseppe Simone , Giovanni Blandino
Bladder cancer (BCa) remains one of the most challenging malignancies in oncology, driven by deep molecular heterogeneity, dynamic tumor evolution and complex tumor–microenvironment interactions. Despite advances in molecular characterization and the introduction of new treatments, translating biological knowledge into meaningful clinical benefits remains a major bottleneck. In recent years, next-generation 3D preclinical models have emerged as essential tools to recapitulate BCa complexity, offering new opportunities to investigate tumor biology and support the development of personalized treatment strategies. This review provides an overview of available 3D models for BCa, discusses their application and highlights their growing integration into clinical trials to guide real-time therapeutic decisions.
{"title":"The role of 3D preclinical models in the Era of precision medicine: A bladder cancer perspective","authors":"Carlotta Frascolla , Riccardo Mastroianni , Giuseppe Simone , Giovanni Blandino","doi":"10.1016/j.gene.2025.149919","DOIUrl":"10.1016/j.gene.2025.149919","url":null,"abstract":"<div><div>Bladder cancer (BCa) remains one of the most challenging malignancies in oncology, driven by deep molecular heterogeneity, dynamic tumor evolution and complex tumor–microenvironment interactions. Despite advances in molecular characterization and the introduction of new treatments, translating biological knowledge into meaningful clinical benefits remains a major bottleneck. In recent years, next-generation 3D preclinical models have emerged as essential tools to recapitulate BCa complexity, offering new opportunities to investigate tumor biology and support the development of personalized treatment strategies. This review provides an overview of available 3D models for BCa, discusses their application and highlights their growing integration into clinical trials to guide real-time therapeutic decisions.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"979 ","pages":"Article 149919"},"PeriodicalIF":2.4,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145616554","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}
Pub Date : 2025-11-23DOI: 10.1016/j.gene.2025.149917
Yunyi Liu, Peiyun Zhuang
Laryngeal leukoplakia represents the most frequent precancerous lesion in laryngeal carcinogenesis, yet its transformation mechanisms remain elusive. By performing scRNA-seq on ten clinical specimens (five leukoplakia lesions across pathological stages, four early carcinomas, and one control), we established the first single-cell atlas of this malignant progression. Computational analysis revealed dynamic microenvironmental shifts dominated by epithelial cells, fibroblasts, and mononuclear phagocytes. We identified two critical epithelial subpopulations: Epi_4 (tumor-like cells), a high-grade dysplasia-specific subpopulation with high malignant potential, and Epi_5 (tumor cells) in carcinoma, which carries a favorable prognostic gene signature (Module 3). Furthermore, Epi_4 showed preferential communication with cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) via the JAG1-NOTCH4 and CXCL5-CXCR1 axes, suggesting actionable therapeutic targets. We also observed the progressive activation of genes involved in redox processes (NQO1, GSTM3, UCHL1, NTRK2) via the KEAP1-NRF2 pathway. This work systematically characterizes the cellular and molecular landscape during laryngeal leukoplakia malignant transformation, providing a framework for future mechanistic studies and early detection strategies.
{"title":"Dynamic tumor microenvironment remodeling from laryngeal leukoplakia to carcinoma revealed by single-cell transcriptomics","authors":"Yunyi Liu, Peiyun Zhuang","doi":"10.1016/j.gene.2025.149917","DOIUrl":"10.1016/j.gene.2025.149917","url":null,"abstract":"<div><div>Laryngeal leukoplakia represents the most frequent precancerous lesion in laryngeal carcinogenesis, yet its transformation mechanisms remain elusive. By performing scRNA-seq on ten clinical specimens (five leukoplakia lesions across pathological stages, four early carcinomas, and one control), we established the first single-cell atlas of this malignant progression. Computational analysis revealed dynamic microenvironmental shifts dominated by epithelial cells, fibroblasts, and mononuclear phagocytes. We identified two critical epithelial subpopulations: Epi_4 (tumor-like cells), a high-grade dysplasia-specific subpopulation with high malignant potential, and Epi_5 (tumor cells) in carcinoma, which carries a favorable prognostic gene signature (Module 3). Furthermore, Epi_4 showed preferential communication with cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) via the JAG1-NOTCH4 and CXCL5-CXCR1 axes, suggesting actionable therapeutic targets. We also observed the progressive activation of genes involved in redox processes (NQO1, GSTM3, UCHL1, NTRK2) via the KEAP1-NRF2 pathway. This work systematically characterizes the cellular and molecular landscape during laryngeal leukoplakia malignant transformation, providing a framework for future mechanistic studies and early detection strategies.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"979 ","pages":"Article 149917"},"PeriodicalIF":2.4,"publicationDate":"2025-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145603115","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}
Pub Date : 2025-11-23DOI: 10.1016/j.gene.2025.149916
Marcelo Arancibia , Jefferson Rojas , M. Leonor Bustamante
Advances in genetics and genomics have transformed our understanding of personality. The observation that personality traits run in families has prompted extensive study into their heritability and underlying genetic architecture. However, there is a significant discrepancy between psychiatric classifications of personality disorders and genomic findings, suggesting a need to reorient these classifications toward a more dimensional, biologically informed perspective. This article reviews key genetic and genomic findings in personality, focusing on the “Big Five” model, which has proven consistency with genomic research. Twin studies estimate heritability accounts for about 40–50 % of personality traits, while the rest of phenotypic variation is explained by the non-shared environment, which influence personality through epigenetic changes. Genome-wide association studies (GWAS) have identified numerous genetic variants on nearly all chromosomes that influence personality traits, particularly neuroticism. These variants are involved in biological pathways such as neurogenesis and neuronal differentiation. GWAS have also revealed significant genetic correlations between personality traits and major psychiatric disorders, supporting a biological continuum between them. This supports the hypothesis which states that a typical behavioral trait is associated with many genetic variants, each contributing a very small effect. Future research should incorporate epigenetic evidence, study genetic interactions, and expand the diversity of study populations beyond European ancestry to improve the generalizability of findings.
{"title":"Heredity and personality: A review of concepts, methods, and evidence","authors":"Marcelo Arancibia , Jefferson Rojas , M. Leonor Bustamante","doi":"10.1016/j.gene.2025.149916","DOIUrl":"10.1016/j.gene.2025.149916","url":null,"abstract":"<div><div>Advances in genetics and genomics have transformed our understanding of personality. The observation that personality traits run in families has prompted extensive study into their heritability and underlying genetic architecture. However, there is a significant discrepancy between psychiatric classifications of personality disorders and genomic findings, suggesting a need to reorient these classifications toward a more dimensional, biologically informed perspective. This article reviews key genetic and genomic findings in personality, focusing on the “Big Five” model, which has proven consistency with genomic research. Twin studies estimate heritability accounts for about 40–50 % of personality traits, while the rest of phenotypic variation is explained by the non-shared environment, which influence personality through epigenetic changes. Genome-wide association studies (GWAS) have identified numerous genetic variants on nearly all chromosomes that influence personality traits, particularly neuroticism. These variants are involved in biological pathways such as neurogenesis and neuronal differentiation. GWAS have also revealed significant genetic correlations between personality traits and major psychiatric disorders, supporting a biological continuum between them. This supports the hypothesis which states that a typical behavioral trait is associated with many genetic variants, each contributing a very small effect. Future research should incorporate epigenetic evidence, study genetic interactions, and expand the diversity of study populations beyond European ancestry to improve the generalizability of findings.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"979 ","pages":"Article 149916"},"PeriodicalIF":2.4,"publicationDate":"2025-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145603455","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}
Pub Date : 2025-11-20DOI: 10.1016/j.gene.2025.149915
Youmei Wu, Xinzhu Li, Junyang Chen, Bo Yang, Xiaojun Yang, Jin Hou
Tooth agenesis (TA), one of the most common craniofacial developmental anomalies, is characterized by the congenital absence of one or more teeth. While numerous genes have been implicated in non-syndromic tooth agenesis (NSTA), its genetic architecture often remains complex. In this study, we investigated the genetic basis of NSTA in a two-generation Chinese family utilizing whole-exome sequencing (WES) complemented by Sanger sequencing. Our analysis revealed a complex segregation pattern of multiple variants. After systematic filtering based on pathogenicity predictions and minor allele frequency (MAF), we identified eight potential contributory variants. These include homozygous missense variants in EDAR (c.1109 T > C), GHR (c.1630A > C), and COL17A1 (c.629C > T), a heterozygous missense variant in CEP152 (c.161C > T), and DSP (c.5213G > A) and three rare heterozygous missense variants in CCDC154 (c.925C > T), FRAS1 (c.9628G > A), and NBAS (c.5095G > A). Notably, the variants in GHR, CCDC154, FRAS1, and NBAS represent potential novel candidate genes for NSTA, thereby expanding the variant spectrum associated with this condition. The co-segregation of these multi-locus variants suggests that inheritance might be complex, perhaps involving oligogenic mechanisms. This points to the possibility of intricate genetic interactions in tooth development, offering new clues about the molecular basis of familial NSTA.
{"title":"Genetic analysis of a Chinese family with non-syndromic tooth agenesis may reveal a potential multi-locus etiology","authors":"Youmei Wu, Xinzhu Li, Junyang Chen, Bo Yang, Xiaojun Yang, Jin Hou","doi":"10.1016/j.gene.2025.149915","DOIUrl":"10.1016/j.gene.2025.149915","url":null,"abstract":"<div><div>Tooth agenesis (TA), one of the most common craniofacial developmental anomalies, is characterized by the congenital absence of one or more teeth. While numerous genes have been implicated in non-syndromic tooth agenesis (NSTA), its genetic architecture often remains complex. In this study, we investigated the genetic basis of NSTA in a two-generation Chinese family utilizing whole-exome sequencing (WES) complemented by Sanger sequencing. Our analysis revealed a complex segregation pattern of multiple variants. After systematic filtering based on pathogenicity predictions and minor allele frequency (MAF), we identified eight potential contributory variants. These include homozygous missense variants in <em>EDAR</em> (c.1109 T > C), <em>GHR</em> (c.1630A > C), and <em>COL17A1</em> (c.629C > T), a heterozygous missense variant in <em>CEP152</em> (c.161C > T), and <em>DSP</em> (c.5213G > A) and three rare heterozygous missense variants in <em>CCDC154</em> (c.925C > T), <em>FRAS1</em> (c.9628G > A), and <em>NBAS</em> (c.5095G > A). Notably, the variants in <em>GHR</em>, <em>CCDC154</em>, <em>FRAS1</em>, and <em>NBAS</em> represent potential novel candidate genes for NSTA, thereby expanding the variant spectrum associated with this condition. The co-segregation of these multi-locus variants suggests that inheritance<!--> <!-->might<!--> <!-->be complex, perhaps involving oligogenic mechanisms. This<!--> <!-->points to the possibility<!--> <!-->of intricate genetic interactions in tooth development, offering new clues about the molecular basis of familial NSTA.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"979 ","pages":"Article 149915"},"PeriodicalIF":2.4,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145582018","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}
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