Pub Date : 2025-11-01DOI: 10.1016/j.gene.2025.149846
Xingyue Xue , Yidan Xu , Xinwei Li , Yalin Zhang , Siyu Wen , Jia Liu , Houhua Li , Zenglin Li , Ying Duan
Crabapple is a horticulturally valuable ornamental plant renowned for its diverse flower and leaf colors, with its aesthetic and economic value closely linked to anthocyanin production. While anthocyanin-mediated pigmentation has been widely studied in fruits and flowers, the regulatory networks governing leaf coloration remain less understood. In this study, we employed Malus spectabilis, which displays natural red/green leaf color variation, as a model to investigate the molecular mechanisms of leaf anthocyanin biosynthesis. We found that the expression of two Arabidopsis ERF4 homologs, MsERF4-like1 and MsERF4-like2, was significantly higher in red leaves compared to green leaves, suggesting coordinated upregulation with key anthocyanin structural genes. Overexpression of MsERF4-like1 and MsERF4-like2 in apple fruit peel enhanced anthocyanin accumulation compared to the empty vector control. Crucially, yeast one-hybrid and dual-luciferase reporter assays demonstrated that both MsERF4-like1 and MsERF4-like2 directly bind the promoter of the anthocyanin structural gene MsCHI, thereby activating its transcription and promoting anthocyanin accumulation. Collectively, these findings reveal that MsERF4-like1 and MsERF4-like2 directly regulate anthocyanin biosynthetic genes to control leaf coloration in M. spectabilis, offering potential targets for genetic improvement of foliage color in ornamental plants.
{"title":"MsERF4-like1/2 transcription factors positively regulate anthocyanin biosynthesis in Malus spectabilis","authors":"Xingyue Xue , Yidan Xu , Xinwei Li , Yalin Zhang , Siyu Wen , Jia Liu , Houhua Li , Zenglin Li , Ying Duan","doi":"10.1016/j.gene.2025.149846","DOIUrl":"10.1016/j.gene.2025.149846","url":null,"abstract":"<div><div>Crabapple is a horticulturally valuable ornamental plant renowned for its diverse flower and leaf colors, with its aesthetic and economic value closely linked to anthocyanin production. While anthocyanin-mediated pigmentation has been widely studied in fruits and flowers, the regulatory networks governing leaf coloration remain less understood. In this study, we employed <em>Malus spectabilis</em>, which displays natural red/green leaf color variation, as a model to investigate the molecular mechanisms of leaf anthocyanin biosynthesis. We found that the expression of two <em>Arabidopsis</em> ERF4 homologs, <em>MsERF4-like1</em> and <em>MsERF4-like2</em>, was significantly higher in red leaves compared to green leaves, suggesting coordinated upregulation with key anthocyanin structural genes. Overexpression of MsERF4-like1 and MsERF4-like2 in apple fruit peel enhanced anthocyanin accumulation compared to the empty vector control. Crucially, yeast one-hybrid and dual-luciferase reporter assays demonstrated that both MsERF4-like1 and MsERF4-like2 directly bind the promoter of the anthocyanin structural gene <em>MsCHI</em>, thereby activating its transcription and promoting anthocyanin accumulation. Collectively, these findings reveal that MsERF4-like1 and MsERF4-like2 directly regulate anthocyanin biosynthetic genes to control leaf coloration in <em>M. spectabilis</em>, offering potential targets for genetic improvement of foliage color in ornamental plants.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"975 ","pages":"Article 149846"},"PeriodicalIF":2.4,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145431034","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 : 2025-11-01DOI: 10.1016/j.gene.2025.149867
Ayelén Emilce López , Paola Locatelli , Jorge Alejandro Simonin , Mariano Nicolás Belaich , Agustina Scharn , Alberto José Crottogini , Fernanda Daniela Olea , María del Rosario Bauzá
Background
Ischemic heart disease is the cardiovascular condition with the highest morbidity and mortality worldwide, highlighting the need for therapies aimed at promoting neovascularization of the ischemic myocardium. Given the involvement of the transcription factor Myeloid ecotropic viral integration site 1 (MEIS1) in the development of the vascular network in vertebrates, we hypothesized that MEIS1 overexpression would induce microvascular proliferation in an ovine model of acute myocardial infarction.
Methods
A baculoviral vector encoding MEIS1 (Bv.Meis1) was designed and injected into the peri-infarct zone of adult sheep with permanent coronary ligation. Control sheep were injected with an empty baculovirus (Bv.Null). One week later, microvascular densities and expression of angiogenic genes were assessed in myocardial tissue samples.
Results
Animals treated with Bv.Meis1 exhibited significantly greater capillary and arteriolar densities as well as a significant increase in the expression of Vegf, Angiogenin, Hif1α, Igf, Fgf2 and Prok2, compared to Bv.Null group. Additionally, overexpression of most of these genes was also found in cultures of neonatal rat cardiomyocytes transduced with Bv.Meis1, and increased tubulogenesis was observed in HMEC-1 cells incubated with supernatants of these cultures. Finally, the vector’s biosafety was demonstrated by the absence of viral DNA expression in tissues remote to the heart.
Conclusions
Intramyocardial injection of a baculovirus encoding MEIS1 promotes overexpression of angiogenic genes which, in turn, induce angio-arteriogenesis in ovine myocardial infarction. Given the highly translational nature of the animal model and the good biosafety profile of the baculoviral vector, this strategy could potentially be useful for patients with ischemic heart disease.
{"title":"Intramyocardial baculovirus-Meis1 gene therapy induces angio-arteriogenesis in sheep with myocardial infarction","authors":"Ayelén Emilce López , Paola Locatelli , Jorge Alejandro Simonin , Mariano Nicolás Belaich , Agustina Scharn , Alberto José Crottogini , Fernanda Daniela Olea , María del Rosario Bauzá","doi":"10.1016/j.gene.2025.149867","DOIUrl":"10.1016/j.gene.2025.149867","url":null,"abstract":"<div><h3>Background</h3><div>Ischemic heart disease is the cardiovascular condition with the highest morbidity and mortality worldwide, highlighting the need for therapies aimed at promoting neovascularization of the ischemic myocardium. Given the involvement of the transcription factor Myeloid ecotropic viral integration site 1 (MEIS1) in the development of the vascular network in vertebrates, we hypothesized that MEIS1 overexpression would induce microvascular proliferation in an ovine model of acute myocardial infarction.</div></div><div><h3>Methods</h3><div>A baculoviral vector encoding MEIS1 (Bv.Meis1) was designed and injected into the <em>peri</em>-infarct zone of adult sheep with permanent coronary ligation. Control sheep were injected with an empty baculovirus (Bv.Null). One week later, microvascular densities and expression of angiogenic genes were assessed in myocardial tissue samples.</div></div><div><h3>Results</h3><div>Animals treated with Bv.Meis1 exhibited significantly greater capillary and arteriolar densities as well as a significant increase in the expression of <em>Vegf</em>, <em>Angiogenin</em>, <em>Hif1α</em>, <em>Igf</em>, <em>Fgf2</em> and <em>Prok2</em>, compared to Bv.Null group. Additionally, overexpression of most of these genes was also found in cultures of neonatal rat cardiomyocytes transduced with Bv.Meis1, and increased tubulogenesis was observed in HMEC-1 cells incubated with supernatants of these cultures. Finally, the vector’s biosafety was demonstrated by the absence of viral DNA expression in tissues remote to the heart.</div></div><div><h3>Conclusions</h3><div>Intramyocardial injection of a baculovirus encoding MEIS1 promotes overexpression of angiogenic genes which, in turn, induce angio-arteriogenesis in ovine myocardial infarction. Given the highly translational nature of the animal model and the good biosafety profile of the baculoviral vector, this strategy could potentially be useful for patients with ischemic heart disease.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"976 ","pages":"Article 149867"},"PeriodicalIF":2.4,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145437710","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 : 2025-10-31DOI: 10.1016/j.gene.2025.149866
Ming-Ren Ma , Xiao Song , Xiao-Ke Wang , Yan Liu , Xiao-Qing Cai , Rong-Rong Zheng , Ming-Hao Liu , Jun Ma , Fei Wang , Ling Ma
Viral myocarditis (VMC) is a prevalent inflammatory cardiac condition, characterized by highly variable clinical manifestations that present significant challenges for early diagnosis and the development of personalized treatment strategies. Consequently, there is an urgent need to develop novel biomarkers and targeted therapeutic approaches to enhance its clinical management. Circulating microRNAs (miRNAs) have emerged as promising candidates for disease diagnosis and treatment due to their stability as intercellular communication molecules and resistance to nuclease degradation. Their significance in various disease contexts has garnered considerable research attention. Recent advancements in high-throughput sequencing technologies, coupled with deep learning and the integration of artificial intelligence (AI) into RNA/protein structure prediction, have improved our understanding of the roles of regulatory networks involving circulating microRNAs in the pathogenesis of viral myocarditis. This systematic review covers recent evidence for the clinical applicability and limitations of the use of circulating miRNAs as specific diagnostic and therapeutic targets for viral myocarditis. It was performed with the aim of establishing a theoretical foundation and strategic framework to improve the precision of this condition’s diagnosis and treatment.
{"title":"Circulating microRNAs in viral myocarditis: Advancements in biological understanding and potential clinical applications","authors":"Ming-Ren Ma , Xiao Song , Xiao-Ke Wang , Yan Liu , Xiao-Qing Cai , Rong-Rong Zheng , Ming-Hao Liu , Jun Ma , Fei Wang , Ling Ma","doi":"10.1016/j.gene.2025.149866","DOIUrl":"10.1016/j.gene.2025.149866","url":null,"abstract":"<div><div>Viral myocarditis (VMC) is a prevalent inflammatory cardiac condition, characterized by highly variable clinical manifestations that present significant challenges for early diagnosis and the development of personalized treatment strategies. Consequently, there is an urgent need to develop novel biomarkers and targeted therapeutic approaches to enhance its clinical management. Circulating microRNAs (miRNAs) have emerged as promising candidates for disease diagnosis and treatment due to their stability as intercellular communication molecules and resistance to nuclease degradation. Their significance in various disease contexts has garnered considerable research attention. Recent advancements in high-throughput sequencing technologies, coupled with deep learning and the integration of artificial intelligence (AI) into RNA/protein structure prediction, have improved our understanding of the roles of regulatory networks involving circulating microRNAs in the pathogenesis of viral myocarditis. This systematic review covers recent evidence for the clinical applicability and limitations of the use of circulating miRNAs as specific diagnostic and therapeutic targets for viral myocarditis. It was performed with the aim of establishing a theoretical foundation and strategic framework to improve the precision of this condition’s diagnosis and treatment.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"975 ","pages":"Article 149866"},"PeriodicalIF":2.4,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145431099","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 : 2025-10-30DOI: 10.1016/j.gene.2025.149865
Wei Zhao, Jinli Tian, Lijuan Yang, Lin Xue, Siyu Chen, Rinmin Ma, Yaling Gu, Dawei Wei, Juan Zhang
Meat quality is a critical factor influencing the sales of chicken. Most plant extracts have been shown to improve meat quality in poultry. This study selected 120 similar-weight (1.5 ± 0.2 kg) 135-day-old Jingyuan chickens, divided them into four groups, and fed them different doses (CON, 0.3 % FCE, 0.6 % FCE, and 0.9 % FCE) of fresh corn extract (FCE) until they were 180-day-old chickens. Fifteen chickens were randomly selected from each group for slaughter performance and meat quality assessment. Combining the transcriptome and metabolome sequencing data of the breast (CON and 0.6 % FCE), the weighted co-expression network analysis (WGCNA) method was used to identify hub genes and key metabolites significantly related to meat quality. The results showed that the 0.6 % FCE group was significantly better than the other groups in terms of slaughter performance and meat quality. Transcriptomic analysis identified differentially expressed genes (DEGs) significantly enriched in mineral absorption, amino sugar and nucleotide sugar metabolism, and phosphonate and phosphinate metabolism. Based on WGCNA, six key DEGs significantly associated with meat quality were selected. Metabolomics analysis identified differentially expressed metabolites (DEMs) significantly enriched in the pathways of secondary bile acid biosynthesis, autophagy, pantothenate and CoA biosynthesis, and beta-alanine metabolism Pearson correlation analysis further revealed correlations between the six key DEGs (YKT6, ENSGALG00010016848, GALK2, COMMD9, EIF2D, and GABPB2) and five key DEMs (1H-Indole-4-carboxaldehyde, Leucylproline, Trimethoprim, Ursodeoxycholic acid, and N.epsilon.-Acetyl-L-lysine). Furthermore, the expression levels and content of these genes and metabolites in the breast muscle of Jingyuan chickens were also assessed.
{"title":"Study on the molecular mechanism of dietary FCE supplementation in regulating chicken meat quality","authors":"Wei Zhao, Jinli Tian, Lijuan Yang, Lin Xue, Siyu Chen, Rinmin Ma, Yaling Gu, Dawei Wei, Juan Zhang","doi":"10.1016/j.gene.2025.149865","DOIUrl":"10.1016/j.gene.2025.149865","url":null,"abstract":"<div><div>Meat quality is a critical factor influencing the sales of chicken. Most plant extracts have been shown to improve meat quality in poultry. This study selected 120 similar-weight (1.5 ± 0.2 kg) 135-day-old Jingyuan chickens, divided them into four groups, and fed them different doses (CON, 0.3 % FCE, 0.6 % FCE, and 0.9 % FCE) of fresh corn extract (FCE) until they were 180-day-old chickens. Fifteen chickens were randomly selected from each group for slaughter performance and meat quality assessment. Combining the transcriptome and metabolome sequencing data of the breast (CON and 0.6 % FCE), the weighted co-expression network analysis (WGCNA) method was used to identify hub genes and key metabolites significantly related to meat quality. The results showed that the 0.6 % FCE group was significantly better than the other groups in terms of slaughter performance and meat quality. Transcriptomic analysis identified differentially expressed genes (DEGs) significantly enriched in mineral absorption, amino sugar and nucleotide sugar metabolism, and phosphonate and phosphinate metabolism. Based on WGCNA, six key DEGs significantly associated with meat quality were selected. Metabolomics analysis identified differentially expressed metabolites (DEMs) significantly enriched in the pathways of secondary bile acid biosynthesis, autophagy, pantothenate and CoA biosynthesis, and beta-alanine metabolism Pearson correlation analysis further revealed correlations between the six key DEGs (<em>YKT6</em>, <em>ENSGALG00010016848</em>, <em>GALK2</em>, <em>COMMD9</em>, <em>EIF2D</em>, and <em>GABPB2</em>) and five key DEMs (1H-Indole-4-carboxaldehyde, Leucylproline, Trimethoprim, Ursodeoxycholic acid, and N.epsilon.-Acetyl-L-lysine). Furthermore, the expression levels and content of these genes and metabolites in the breast muscle of Jingyuan chickens were also assessed.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"977 ","pages":"Article 149865"},"PeriodicalIF":2.4,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145421732","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 : 2025-10-30DOI: 10.1016/j.gene.2025.149855
George A. Addy , Quan Wang , Hong Chen, Wijdan Abdu, Mohamed Diaby, Xin Chen, Emmanuel Asare, Bo Gao, Chengyi Song
Mutator-like elements (MULEs) were thought to be plant-specific, but research showed that MULEs are present in diverse eukaryotes including fungi, amoeba, worms etc. This study investigates the distribution, abundance, diversity and evolutionary dynamics of MULEs within the genomes of flatworms (Platyhelminthes), roundworms (Nematodes) and other worms (Acanthocephala, Annelida, Dicyemida and Nemertea). Multiples of divergent MULE families were identified and characterized with structural variability across the taxa. Few MULEs detected exhibit low Kimura divergence (KD) values, suggesting a recent transpositional capability. Structural analysis highlighted conserved catalytic domains (DDE), diverse terminal inverted repeats (TIRs) and their potential roles in shaping the genomes architecture. Functional implications of MULE prevalence in worms on host-parasitic interactions were explored. The evolutionary dynamics of MULEs within the taxa and their probable impact on the host species were inquired. This study discovered 113 types of MULE transposons (Tn) from 46 genomes of worm species researched. The MULEs detected are widely and unevenly distributed across Nematodes, Platyhelminthes, Acanthocephala, Annelida, Dicyemida and Nemertea. 25 MULE types harbour 358 full-length MULE copies and 284 intact MULE copies which encode functional transposases ≥300 amino acids (aa). The MULEs possess a wide size range, spanning from 1323 to 4819 base pairs (bp). They encode transposases (116–750 aa) with distinct TIRs (41–950 bp). Few MULEs detected have young insertion ages. This phenomenon indicates that these MULEs may be recent genome invaders with dynamic transposition energies. Transposons such as MULE-Mear-1, MULE-Meja-2 and MULE-Trsu-1 displayed multiple amplification waves reflecting their ongoing energetic transposition within the host. Only few transposons (<22 %) were discovered to harbour intact MULE copies ≥5. However, three MULE candidates were chosen for activity validation in human cells. The transposon (MULE-Apca-1) was designated as Acali for testing and evaluation. After a successful drug selection, the Acali transposase derived from the earthworm (Aporrectodea caliginosa) showed significant transposition activity relative to the hyperactive PB transposon. This study uncovered that MULEs are highly abundant in flatworms than roundworms and other worms. Nevertheless, MULE remnants exhibited wide distribution and diversity in Nematodes and Annelida (other worms) than Platyhelminthes. These findings emphasized the evolutionary importance of MULEs in worms with many new families yet to be discovered to enrich our understanding on the roles of DNA transposons in genome plasticity.
Mutator-like elements （MULEs）被认为是植物特异性的，但研究表明MULEs存在于多种真核生物中，包括真菌、变形虫、蠕虫等。本研究探讨了扁虫（Platyhelminthes）、蛔虫（Nematodes）和其他蠕虫（棘头纲、节虫纲、双尾纲和Nemertea）基因组中MULEs的分布、丰度、多样性和进化动态。鉴定了多个不同的MULE家族，并以不同分类群的结构变异性为特征。少数检测到的骡子表现出较低的木村散度（KD）值，表明其最近具有换位能力。结构分析强调了保守的催化结构域（DDE）、不同的末端倒置重复序列（TIRs）及其在塑造基因组结构中的潜在作用。探讨了MULE在蠕虫中流行对宿主-寄生虫相互作用的功能意义。探讨了该分类群中MULEs的进化动态及其对宿主物种的可能影响。本研究从46种蠕虫基因组中发现了113种MULE转座子（Tn）。检测到的MULE分布广泛且不均匀，分布于线虫、白蛉、棘头纲、节肢纲、双肢纲和内默亚目，其中25个类型含有358个全长的MULE拷贝和284个完整的MULE拷贝，编码的功能性转座酶≥300个氨基酸（aa）。MULEs的大小范围很广，从1323到4819个碱基对（bp）不等。它们编码的转座酶（116-750 aa）具有不同的TIRs （41-950 bp）。检测到的骡子很少有年轻的插入年龄。这一现象表明这些mule可能是具有动态转位能量的近期基因组入侵者。转座子如MULE-Mear-1、MULE-Meja-2和MULE-Trsu-1表现出多重扩增波，反映了它们在宿主体内持续的能量转座。只有少数转座子（< 22%）被发现携带完整的≥5个MULE拷贝。然而，选择了三种MULE候选药物在人细胞中进行活性验证。该转座子（MULE-Apca-1）被指定为Acali进行检测和评价。在成功的药物选择后，来自蚯蚓（Aporrectodea caliginosa）的Acali转座酶相对于过度活跃的PB转座子显示出显著的转座活性。该研究发现，扁虫中MULEs的含量比蛔虫和其他蠕虫高。然而，MULE残留物在线虫和环节动物（其他蠕虫）中的分布和多样性比在白蛉中更为广泛。这些发现强调了MULEs在许多新家族尚未被发现的蠕虫中的进化重要性，从而丰富了我们对DNA转座子在基因组可塑性中的作用的理解。
{"title":"Evolution of Mutator transposons in the genomes of worms","authors":"George A. Addy , Quan Wang , Hong Chen, Wijdan Abdu, Mohamed Diaby, Xin Chen, Emmanuel Asare, Bo Gao, Chengyi Song","doi":"10.1016/j.gene.2025.149855","DOIUrl":"10.1016/j.gene.2025.149855","url":null,"abstract":"<div><div>Mutator-like elements (MULEs) were thought to be plant-specific, but research showed that MULEs are present in diverse eukaryotes including fungi, amoeba, worms etc. This study investigates the distribution, abundance, diversity and evolutionary dynamics of MULEs within the genomes of flatworms (Platyhelminthes), roundworms (Nematodes) and other worms (Acanthocephala, Annelida, Dicyemida and Nemertea). Multiples of divergent MULE families were identified and characterized with structural variability across the taxa. Few MULEs detected exhibit low Kimura divergence (KD) values, suggesting a recent transpositional capability. Structural analysis highlighted conserved catalytic domains (DDE), diverse terminal inverted repeats (TIRs) and their potential roles in shaping the genomes architecture. Functional implications of MULE prevalence in worms on host-parasitic interactions were explored. The evolutionary dynamics of MULEs within the taxa and their probable impact on the host species were inquired. This study discovered 113 types of MULE transposons (Tn) from 46 genomes of worm species researched. The MULEs detected are widely and unevenly distributed across Nematodes, Platyhelminthes, Acanthocephala, Annelida, Dicyemida and Nemertea. 25 MULE types harbour 358 full-length MULE copies and 284 intact MULE copies which encode functional transposases ≥300 amino acids (aa). The MULEs possess a wide size range, spanning from 1323 to 4819 base pairs (bp). They encode transposases (116–750 aa) with distinct TIRs (41–950 bp). Few MULEs detected have young insertion ages. This phenomenon indicates that these MULEs may be recent genome invaders with dynamic transposition energies. Transposons such as <em>MULE-Mear-1</em>, <em>MULE-Meja-2</em> and <em>MULE-Trsu-1</em> displayed multiple amplification waves reflecting their ongoing energetic transposition within the host. Only few transposons (<22 %) were discovered to harbour intact MULE copies ≥5. However, three MULE candidates were chosen for activity validation in human cells. The transposon (<em>MULE-Apca-1</em>) was designated as <em>Acali</em> for testing and evaluation. After a successful drug selection, the Acali transposase derived from the earthworm (<em>Aporrectodea caliginosa</em>) showed significant transposition activity relative to the hyperactive PB transposon. This study uncovered that MULEs are highly abundant in flatworms than roundworms and other worms. Nevertheless, MULE remnants exhibited wide distribution and diversity in Nematodes and Annelida (other worms) than Platyhelminthes. These findings emphasized the evolutionary importance of MULEs in worms with many new families yet to be discovered to enrich our understanding on the roles of DNA transposons in genome plasticity.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"975 ","pages":"Article 149855"},"PeriodicalIF":2.4,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145415414","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 : 2025-10-28DOI: 10.1016/j.gene.2025.149858
Jianbo Wu , Tong Yin , Zhiguo Zhang , Ruili Yin , Elsayed Metwally , Kun Li , Yongsong Xu , Hongling Zhao , Shuwen Zheng , Lingling Wei , Lijie Zhang , Yan Wang , Longyan Yang
Background
Diabetic kidney disease (DKD) is a major microvascular complication of diabetes. Current diagnostic markers (e.g., UACR, eGFR) exhibit limitations in sensitivity and specificity, underscoring the need for novel approaches.
Methods
We integrated single-cell RNA sequencing (scRNA-seq) of kidney tissues from 30 individuals (18 healthy, 12 DKD) with serum proteomics data. Cellular heterogeneity and dysregulated pathways were analyzed using Seurat and pathway enrichment analyses. Intercellular communication networks were deciphered via tensor-cell2cell. A LASSO model identified hub genes, followed by robust validation across independent bulk RNA-seq cohorts (Nephrectomy and Nephroseq). Integration with proteomics prioritized three candidate biomarkers—IGFBP2, B2M, and CST3— which were further assessed in murine DKD models (STZ/HFD-induced) and clinical serum samples (n = 139). Drug-target interactions were predicted using ChEMBL and validated by molecular docking.
Results
(1) scRNA-seq revealed aberrant activation of immune pathways and enhanced tubule cell repair in DKD. (2) Cell-cell communication analysis identified 43 hub genes, with 8 genes showing consistent upregulation in glomerular and tubular compartments. (3) Integration of proteomics and transcriptomics pinpointed three serum biomarkers-IGFBP2, B2M, CST3. (4) Longitudinal validation in STZ-induced murine models (n = 16) and human clinical samples (n = 139) confirmed progressive, stage-dependent elevation of all three biomarkers, with late-stage DKD showing the most pronounced elevation versus controls (p < 0.001). (5) Molecular docking predicted high-affinity binding of pramlintide acetate to CST3/IGFBP2 and rivipansel to B2M.
Conclusion
Through a multi-omics approach, we identified IGFBP2/B2M/CST3 as a non-invasive biomarker panel for DKD progression, highlighting their roles as both diagnostic markers and therapeutic targets.
{"title":"Multi-Omics discovery and clinical validation of IGFBP2, B2M, and CST3 as a serum biomarker panel for diabetic kidney disease progression","authors":"Jianbo Wu , Tong Yin , Zhiguo Zhang , Ruili Yin , Elsayed Metwally , Kun Li , Yongsong Xu , Hongling Zhao , Shuwen Zheng , Lingling Wei , Lijie Zhang , Yan Wang , Longyan Yang","doi":"10.1016/j.gene.2025.149858","DOIUrl":"10.1016/j.gene.2025.149858","url":null,"abstract":"<div><h3>Background</h3><div>Diabetic kidney disease (DKD) is a major microvascular complication of diabetes. Current diagnostic markers (e.g., UACR, eGFR) exhibit limitations in sensitivity and specificity, underscoring the need for novel approaches.</div></div><div><h3>Methods</h3><div>We integrated single-cell RNA sequencing (scRNA-seq) of kidney tissues from 30 individuals (18 healthy, 12 DKD) with serum proteomics data. Cellular heterogeneity and dysregulated pathways were analyzed using Seurat and pathway enrichment analyses. Intercellular communication networks were deciphered via tensor-cell2cell. A LASSO model identified hub genes, followed by robust validation across independent bulk RNA-seq cohorts (Nephrectomy and Nephroseq). Integration with proteomics prioritized three candidate biomarkers—IGFBP2, B2M, and CST3— which were further assessed in murine DKD models (STZ/HFD-induced) and clinical serum samples (n = 139). Drug-target interactions were predicted using ChEMBL and validated by molecular docking.</div></div><div><h3>Results</h3><div>(1) scRNA-seq revealed aberrant activation of immune pathways and enhanced tubule cell repair in DKD. (2) Cell-cell communication analysis identified 43 hub genes, with 8 genes showing consistent upregulation in glomerular and tubular compartments. (3) Integration of proteomics and transcriptomics pinpointed three serum biomarkers-IGFBP2, B2M, CST3. (4) Longitudinal validation in STZ-induced murine models (n = 16) and human clinical samples (n = 139) confirmed progressive, stage-dependent elevation of all three biomarkers, with late-stage DKD showing the most pronounced elevation versus controls (p < 0.001). (5) Molecular docking predicted high-affinity binding of pramlintide acetate to CST3/IGFBP2 and rivipansel to B2M.</div></div><div><h3>Conclusion</h3><div>Through a multi-omics approach, we identified IGFBP2/B2M/CST3 as a non-invasive biomarker panel for DKD progression, highlighting their roles as both diagnostic markers and therapeutic targets.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"978 ","pages":"Article 149858"},"PeriodicalIF":2.4,"publicationDate":"2025-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145408644","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 : 2025-10-27DOI: 10.1016/j.gene.2025.149856
Elena M. Rimskaya , Svetlana N. Nasonova , Alexey N. Meshkov , Veronika V. Daniel , Elena A. Zelenova , Irina H. Dzhumaniiazova , Nayana A. Kumar , A. Yu. Fedorov , Sergey I. Mitrofanov , Mikhail V. Ivanov , Daria A. Kashtanova , V.S. Yudin , V.V. Makarov , Anton A. Keskinov , Kristina N. Kozaeva , Anastasia I. Loginova , Nataliua. V. Gomyranova , Yulia S. Vorobieva , Igor V. Zhirov , Sergey M. Yudin , Sergey A. Boytsov
Aim
To analyze the genotype-phenotype associations in huge specialized cohort of inpatients with cardiac disease.
Materials and methods
The whole-genome sequencing data from 4,856 inpatients admitted to the hospital with various cardiovascular diseases were analyzed for pathogenic (PV), likely pathogenic (LPV), and variants of uncertain significance (VUS) in 27 genes from ACMG SF v3.1 list for reporting secondary findings associated with arrhythmias and cardiomyopathies. The carriers of detected gene variants were assessed for full, incomplete, and overlapping phenotypic expressions.
Results
267 gene variants were identified in 261 (5.37 % of the overall sample) participants: 255 were single-variant carriers and six were two-variant carriers. Among them, 20 (7.5 %) had PVs, 149 (55.8 %) had LPVs, and 98 (36.7 %) had VUSs. 18 variants (6.7 %) were detected in genes associated with arrhythmias; 73 variants (27.3 %) were detected in genes associated with cardiomyopathies. The majority of variants (n = 176; 65.9 %) were located in the genes, associated with both cardiomyopathies and arrhythmias. The most prevalent were variants in the TTN (n = 128). The full penetrance of PVs/LPVs was 37.5 % in genes associated with arrhythmias, 52.4 % in genes associated with cardiomyopathies, and 16.9 % in genes ssociated with both arrhythmias and cardiomyopathies. Overall, full phenotypic expression was observed in 36 out of 169P/LP variant carriers (0.74 % of whole sample). The analyses revealed previously unknown genotype-phenotypic associations potentially indicating an overlap syndrome, such as DCM and HCM linked to variants in TRDN.
Conclusion
The research conducted in cohort of inpatients with cardiac diseases provided crucial information about the prevalence and penetrance of genetic variants and allowed to describe previously unknown genotype-phenotypic associations.
{"title":"Cardiomyopathies, heart rhythm and conduction disorders as phenotypic manifestation of genetic variants in large cohort of cardiac patients: results of whole-genome study","authors":"Elena M. Rimskaya , Svetlana N. Nasonova , Alexey N. Meshkov , Veronika V. Daniel , Elena A. Zelenova , Irina H. Dzhumaniiazova , Nayana A. Kumar , A. Yu. Fedorov , Sergey I. Mitrofanov , Mikhail V. Ivanov , Daria A. Kashtanova , V.S. Yudin , V.V. Makarov , Anton A. Keskinov , Kristina N. Kozaeva , Anastasia I. Loginova , Nataliua. V. Gomyranova , Yulia S. Vorobieva , Igor V. Zhirov , Sergey M. Yudin , Sergey A. Boytsov","doi":"10.1016/j.gene.2025.149856","DOIUrl":"10.1016/j.gene.2025.149856","url":null,"abstract":"<div><h3>Aim</h3><div>To analyze the genotype-phenotype associations in huge specialized cohort of inpatients with cardiac disease.</div></div><div><h3>Materials and methods</h3><div>The whole-genome sequencing data from 4,856 inpatients admitted to the hospital with various cardiovascular diseases were analyzed for pathogenic (PV), likely pathogenic (LPV), and variants of uncertain significance (VUS) in 27 genes from ACMG SF v3.1 list for reporting secondary findings associated with arrhythmias and cardiomyopathies. The carriers of detected gene variants were assessed for full, incomplete, and overlapping phenotypic expressions.</div></div><div><h3>Results</h3><div>267 gene variants were identified in 261 (5.37 % of the overall sample) participants: 255 were single-variant carriers and six were two-variant carriers. Among them, 20 (7.5 %) had PVs, 149 (55.8 %) had LPVs, and 98 (36.7 %) had VUSs. 18 variants (6.7 %) were detected in genes associated with arrhythmias; 73 variants (27.3 %) were detected in genes associated with cardiomyopathies. The majority of variants (n = 176; 65.9 %) were located in the genes, associated with both cardiomyopathies and arrhythmias. The most prevalent were variants in the <em>TTN</em> (n = 128). The full penetrance of PVs/LPVs was 37.5 % in genes associated with arrhythmias, 52.4 % in genes associated with cardiomyopathies, and 16.9 % in genes ssociated with both arrhythmias and cardiomyopathies. Overall, full phenotypic expression was observed in 36 out of 169P/LP variant carriers (0.74 % of whole sample). The analyses revealed previously unknown genotype-phenotypic associations potentially indicating an overlap syndrome, such as DCM and HCM linked to variants in <em>TRDN</em>.</div></div><div><h3>Conclusion</h3><div>The research conducted in cohort of inpatients with cardiac diseases provided crucial information about the prevalence and penetrance of genetic variants and allowed to describe previously unknown genotype-phenotypic associations.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"974 ","pages":"Article 149856"},"PeriodicalIF":2.4,"publicationDate":"2025-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145400433","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 : 2025-10-26DOI: 10.1016/j.gene.2025.149854
Xindi Chen , Tengyu Wang , Chunxia Liu , Wa Gao , Weijie Wu , Wenlong Wang
Background
Circular RNAs (circRNAs) are increasingly recognized as important regulators of splicing, transcription and gene expression, and may contribute to drug resistance. The purpose of this study was to investigate the potential roles of circRNAs in the development of albendazole (ABZ) resistance in Haemonchus contortus (H. contortus). By analysing the numbers, species, structural characteristics and functions of circRNAs, we constructed regulatory networks to provide insight into circRNA-mediated mechanisms associated with ABZ resistance.
Methods
In this study, ABZ-sensitive (ABZ-S) strains, ABZ-resistant (ABZ-RA) strains and ABZ-resistant treatment (ABZ-RB) strains of H. contortus were subjected to high-throughput sequencing and cDNA library construction with the Illumina HiSeqTM 4000 platform. The find_circ software was used to predict circRNAs on the basis of quality-control data, and the source genes of differentially expressed circRNAs (DEcircRNAs) were annotated through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Mireap, TargetScan, Miranda and miRTarBase (version 6.1) were applied to predict the interactions of miRNAs and mRNAs with DEcircRNAs, and OriginPro software was used to visualize the circRNA‒miRNA‒mRNA networks. Nine DEcircRNAs were randomly selected from the comparisons, and their expression was validated by quantitative real-time polymerase chain reaction (qRT‒PCR) to assess the consistency with RNA-seq data.
Results
A total of 5695 circRNAs were identified across the three strain comparisons, with lengths ranging from 126 to 95,630 nt. Among them, 364, 252 and 311unique DEcircRNAs were identified in ABZ-S, ABZ-RA, ABZ-RB, respectively. These DEcircRNAs were associated with 1369 parental genes involved in 974 GO terms and 326 KEGG pathways, including 86 metabolic pathways. Complex competitive endogenous RNA (ceRNA) regulatory networks were constructed among DEcircRNAs, differentially expressed microRNAs (DEmiRNAs), and differentially expressed messenger RNAs (DEmRNAs). The ceRNA network comprised 110 DEcircRNAs, 41 DEmiRNAs and 10 DEmRNAs, of which 35 were related to metabolism and 37 to organismal systems. Validation experiments confirmed expression differences for nine DEcircRNAs.
Conclusions
The high-throughput identification of DEcircRNAs in drug-resistant strains suggests that some circRNAs may participate in the development of ABZ resistance by regulating source genes and functioning as ceRNAs. These regulatory processes may involve pathways such as ABC transporters and drug metabolism-cytochrome P450.
{"title":"Dynamic expression and functional analysis of circRNAs during albendazole resistance of Haemonchus contortus","authors":"Xindi Chen , Tengyu Wang , Chunxia Liu , Wa Gao , Weijie Wu , Wenlong Wang","doi":"10.1016/j.gene.2025.149854","DOIUrl":"10.1016/j.gene.2025.149854","url":null,"abstract":"<div><h3>Background</h3><div>Circular RNAs (circRNAs) are increasingly recognized as important regulators of splicing, transcription and gene expression, and may contribute to drug resistance. The purpose of this study was to investigate the potential roles of circRNAs in the development of albendazole (ABZ) resistance in <em>Haemonchus contortus</em> (<em>H. contortus</em>). By analysing the numbers, species, structural characteristics and functions of circRNAs, we constructed regulatory networks to provide insight into circRNA-mediated mechanisms associated with ABZ resistance.</div></div><div><h3>Methods</h3><div>In this study, ABZ-sensitive (ABZ-S) strains, ABZ-resistant (ABZ-RA) strains and ABZ-resistant treatment (ABZ-RB) strains of <em>H. contortus</em> were subjected to high-throughput sequencing and cDNA library construction with the Illumina HiSeq<sup>TM</sup> 4000 platform. The find_circ software was used to predict circRNAs on the basis of quality-control data, and the source genes of differentially expressed circRNAs (DEcircRNAs) were annotated through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Mireap, TargetScan, Miranda and miRTarBase (version 6.1) were applied to predict the interactions of miRNAs and mRNAs with DEcircRNAs, and OriginPro software was used to visualize the circRNA‒miRNA‒mRNA networks. Nine DEcircRNAs were randomly selected from the comparisons, and their expression was validated by quantitative real-time polymerase chain reaction (qRT‒PCR) to assess the consistency with RNA-seq data.</div></div><div><h3>Results</h3><div>A total of 5695 circRNAs were identified across the three strain comparisons, with lengths ranging from 126 to 95,630 nt. Among them, 364, 252 and 311unique DEcircRNAs were identified in ABZ-S, ABZ-RA, ABZ-RB, respectively. These DEcircRNAs were associated with 1369 parental genes involved in 974 GO terms and 326 KEGG pathways, including 86 metabolic pathways. Complex competitive endogenous RNA (ceRNA) regulatory networks were constructed among DEcircRNAs, differentially expressed microRNAs (DEmiRNAs), and differentially expressed messenger RNAs (DEmRNAs). The ceRNA network comprised 110 DEcircRNAs, 41 DEmiRNAs and 10 DEmRNAs, of which 35 were related to metabolism and 37 to organismal systems. Validation experiments confirmed expression differences for nine DEcircRNAs.</div></div><div><h3>Conclusions</h3><div>The high-throughput identification of DEcircRNAs in drug-resistant strains suggests that some circRNAs may participate in the development of ABZ resistance by regulating source genes and functioning as ceRNAs. These regulatory processes may involve pathways such as ABC transporters and drug metabolism-cytochrome P450.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"974 ","pages":"Article 149854"},"PeriodicalIF":2.4,"publicationDate":"2025-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145388526","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 : 2025-10-26DOI: 10.1016/j.gene.2025.149845
Dongmei Yang , Yaping Song , Hongfang Gong , Chao Jiang , Ruopu Jiao , Yilun Ma , Sayed Haidar Abbas Raza , Sameer Dinkar Pant , Yun Ma , Guijie Zhang , Linsen Zan , Sihu Wang , Jiupan Zhang , Dawei Wei
Intramuscular fat (IMF) is a critical indicator affecting meat quality, whose formation and deposition are influenced not only by the cellular microenvironment but also by the coordinated regulation of multiple genes. During this process, long non-coding RNAs (lncRNAs) can competitively bind miRNAs through a molecular sponge mechanism, thereby participating in the regulation of adipocyte growth and further influencing IMF deposition. Therefore, lncRNA sequencing was performed using a bovine skeletal muscle–intramuscular adipocyte co-culture model. Analysis revealed 99 differentially expressed (DE) lncRNAs. To further investigate the regulatory functions of lncRNAs, antisense, cis-acting, and trans-acting target prediction analyses were performed. These analyses identified 4 antisense, 7 cis-acting, and 98 trans-acting DE lncRNA-mRNA interaction pairs. Subsequently, a competing endogenous RNA (ceRNA) network encompassing 260 potential interactions was constructed. Among these, the 20 highest-confidence interactions involved 8 DE-lncRNAs, 11 miRNAs, and 7 mRNAs. These findings establish a foundation for elucidating molecular mechanisms of lncRNA-mediated IMF deposition regulation in cattle via ceRNA pathways.
{"title":"Critical lncRNA screening and ceRNA network Construction in bovine skeletal muscle cells and intramuscular adipocytes co-culture model","authors":"Dongmei Yang , Yaping Song , Hongfang Gong , Chao Jiang , Ruopu Jiao , Yilun Ma , Sayed Haidar Abbas Raza , Sameer Dinkar Pant , Yun Ma , Guijie Zhang , Linsen Zan , Sihu Wang , Jiupan Zhang , Dawei Wei","doi":"10.1016/j.gene.2025.149845","DOIUrl":"10.1016/j.gene.2025.149845","url":null,"abstract":"<div><div>Intramuscular fat (IMF) is a critical indicator affecting meat quality, whose formation and deposition are influenced not only by the cellular microenvironment but also by the coordinated regulation of multiple genes. During this process, long non-coding RNAs (lncRNAs) can competitively bind miRNAs through a molecular sponge mechanism, thereby participating in the regulation of adipocyte growth and further influencing IMF deposition. Therefore, lncRNA sequencing was performed using a bovine skeletal muscle–intramuscular adipocyte co-culture model. Analysis revealed 99 differentially expressed (DE) lncRNAs. To further investigate the regulatory functions of lncRNAs, antisense,<!--> <em>cis</em>-acting, and<!--> <em>trans</em>-acting target prediction analyses were performed. These analyses identified 4 antisense, 7<!--> <em>cis</em>-acting, and 98<!--> <em>trans-</em>acting DE lncRNA-mRNA interaction pairs. Subsequently, a competing endogenous RNA (ceRNA) network encompassing 260 potential interactions was constructed. Among these, the 20 highest-confidence interactions involved 8 DE-lncRNAs, 11 miRNAs, and 7 mRNAs. These findings establish a foundation for elucidating molecular mechanisms of lncRNA-mediated IMF deposition regulation in cattle via ceRNA pathways.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"974 ","pages":"Article 149845"},"PeriodicalIF":2.4,"publicationDate":"2025-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145388546","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 : 2025-10-26DOI: 10.1016/j.gene.2025.149853
Jiadi Wang , Zhirui Zhang , Yue Liu , Beiting Zong , Yixuan Lu , Yuhang Li , Jing Yao
<div><h3>Background</h3><div>Dry Eye Disease (DED) is an ocular surface disease characterized by reduced tear secretion, abnormal fluid dynamics, and decreased tear quality, leading to instability of the tear film. It is accompanied by eye discomfort, visual impairment, and ocular surface tissue damage. DED is not only associated with the death of corneal epithelial cells but also involves damage to multiple ocular surface tissues, including the meibomian glands, lacrimal glands, conjunctival cells, and goblet cells. Ferroptosis plays a role in corneal epithelial cell death and keratopathy, but its underlying mechanisms remain unclear and require further investigation.</div></div><div><h3>Methods</h3><div>This study utilized the GSE208297 dataset (from the Gene Expression Omnibus, GEO) to analyze the gene expression profiles of Mus musculus with DED. Five untreated DED samples and five normal control samples were selected for differential gene expression analysis to identify ferroptosis-related differentially expressed genes (FRDEGs). Based on these FRDEGs, comparative gene expression analysis, functional enrichment analysis, and small-molecule interaction network analysis were conducted. Additionally, gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were performed, and immune infiltration analysis was conducted. A rat model of DED was induced using benzalkonium chloride (Benzalkonium chloride, 0.2 % solution, 5 µl, twice daily for 15 days). The tear secretion was assessed by the Schirmer I test, and structural changes in corneal tissue were observed by hematoxylin and eosin (HE) staining. Mitochondrial changes were examined by transmission electron microscopy (TEM), and ferroptosis was confirmed using malondialdehyde (MDA) and glutathione (GSH) kits. RT-PCR was used for the validation of gene expression analysis, confirming the mRNA expression changes of 8 key genes in the corneal tissue of DED rats.</div></div><div><h3>Results</h3><div>Differential gene expression analysis identified 136 genes with abnormal expression. After intersecting these genes with 833 known ferroptosis-related genes, 13 FRDEGs were identified. These genes were primarily enriched in functions related to muscle tissue development, regulation of white blood cell differentiation, positive regulation of apoptosis signaling pathways, and inflammatory response regulation, as well as KEGG pathways such as MAPK, TNF, and IL-17 signaling. Immune cell infiltration analysis revealed significant differences in immune cell infiltration between DED and control groups, with CD8 T cells, macrophages, and NK cells showing correlations with the expression of FRDEGs. In the small-molecule interaction network analysis, eight key genes (ARNTL, ATF3, CCL5, JUN, KRT14, MYC, NR4A1, and TNF) exhibited strong interaction relationships with other small molecules. RT-PCR verification confirmed significant mRNA expression changes of these eight key genes in the corneal tissu
{"title":"Identification of ferroptosis-related genes in dry eye disease and their effects on inflammatory response and immune infiltration","authors":"Jiadi Wang , Zhirui Zhang , Yue Liu , Beiting Zong , Yixuan Lu , Yuhang Li , Jing Yao","doi":"10.1016/j.gene.2025.149853","DOIUrl":"10.1016/j.gene.2025.149853","url":null,"abstract":"<div><h3>Background</h3><div>Dry Eye Disease (DED) is an ocular surface disease characterized by reduced tear secretion, abnormal fluid dynamics, and decreased tear quality, leading to instability of the tear film. It is accompanied by eye discomfort, visual impairment, and ocular surface tissue damage. DED is not only associated with the death of corneal epithelial cells but also involves damage to multiple ocular surface tissues, including the meibomian glands, lacrimal glands, conjunctival cells, and goblet cells. Ferroptosis plays a role in corneal epithelial cell death and keratopathy, but its underlying mechanisms remain unclear and require further investigation.</div></div><div><h3>Methods</h3><div>This study utilized the GSE208297 dataset (from the Gene Expression Omnibus, GEO) to analyze the gene expression profiles of Mus musculus with DED. Five untreated DED samples and five normal control samples were selected for differential gene expression analysis to identify ferroptosis-related differentially expressed genes (FRDEGs). Based on these FRDEGs, comparative gene expression analysis, functional enrichment analysis, and small-molecule interaction network analysis were conducted. Additionally, gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were performed, and immune infiltration analysis was conducted. A rat model of DED was induced using benzalkonium chloride (Benzalkonium chloride, 0.2 % solution, 5 µl, twice daily for 15 days). The tear secretion was assessed by the Schirmer I test, and structural changes in corneal tissue were observed by hematoxylin and eosin (HE) staining. Mitochondrial changes were examined by transmission electron microscopy (TEM), and ferroptosis was confirmed using malondialdehyde (MDA) and glutathione (GSH) kits. RT-PCR was used for the validation of gene expression analysis, confirming the mRNA expression changes of 8 key genes in the corneal tissue of DED rats.</div></div><div><h3>Results</h3><div>Differential gene expression analysis identified 136 genes with abnormal expression. After intersecting these genes with 833 known ferroptosis-related genes, 13 FRDEGs were identified. These genes were primarily enriched in functions related to muscle tissue development, regulation of white blood cell differentiation, positive regulation of apoptosis signaling pathways, and inflammatory response regulation, as well as KEGG pathways such as MAPK, TNF, and IL-17 signaling. Immune cell infiltration analysis revealed significant differences in immune cell infiltration between DED and control groups, with CD8 T cells, macrophages, and NK cells showing correlations with the expression of FRDEGs. In the small-molecule interaction network analysis, eight key genes (ARNTL, ATF3, CCL5, JUN, KRT14, MYC, NR4A1, and TNF) exhibited strong interaction relationships with other small molecules. RT-PCR verification confirmed significant mRNA expression changes of these eight key genes in the corneal tissu","PeriodicalId":12499,"journal":{"name":"Gene","volume":"974 ","pages":"Article 149853"},"PeriodicalIF":2.4,"publicationDate":"2025-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145370955","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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