Genes & genomics最新文献

{"title":"A pan-cancer analysis unveiling the function of NR4A family genes in tumor immune microenvironment, prognosis, and drug response.","authors":"Seong-Woo Park, Mi-Ryung Han","doi":"10.1007/s13258-024-01539-1","DOIUrl":"10.1007/s13258-024-01539-1","url":null,"abstract":"<p><strong>Background: </strong>NR4A family genes play crucial roles in cancers. However, the role of NR4A family genes in cancers remains paradoxical as they promote or suppress tumorigenesis.</p><p><strong>Objective: </strong>We aimed to conduct comprehensive analyses of the association between the expression of NR4A family genes and tumor microenvironment (TME) based on bioinformatics methods.</p><p><strong>Methods: </strong>We collected RNA-seq data from 33 cancer types and 20 normal tissue sites from the TCGA and GTEx databases. Expression patterns of NR4A family genes and their associations with DNA methylation, miRNA, overall survival, drug responses, and tumor microenvironment were investigated.</p><p><strong>Results: </strong>Significant downregulation of all NR4A family genes was observed in 15 cancer types. DNA promoter methylation and expression of NR4A family genes were negatively correlated in five cancers. The expression of 10 miRNAs targeting NR4A family genes was negatively correlated with the expression of NR4A family genes. High expression of all NR4A family genes was associated with poor prognosis in stomach adenocarcinoma and increased expressions of NR4A2 and NR4A3 were associated with poor prognosis in adrenocortical carcinoma. In addition, we found an elevated expression of NR4A2, which enhances the response to various chemotherapeutic drugs, whereas NR4A3 decreases drug sensitivity. Interestingly, in breast cancer, NR4A3 was significantly associated with C2 (IFN-γ dominant), C3 (inflammatory), and C6 (TGF-β dominant) immune subtypes and infiltrated immune cell types, implying both oncogenic and tumor-suppressive functions of NR4A3 in breast cancer.</p><p><strong>Conclusion: </strong>The NR4A family genes have the potential to serve as a diagnostic, prognostic, and immunological marker of human cancers.</p>","PeriodicalId":12675,"journal":{"name":"Genes & genomics","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141554695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring oral bacterial compositional network in two oral disease groups using a convergent approach of NGS-molecular diagnostics.","authors":"Jinuk Jeong, Kung Ahn, Kyeongeui Yun, Minseo Kim, Yeseul Choi, Miyang Han, Seyoung Mun, Yeon-Tae Kim, Kyung Eun Lee, Moon-Young Kim, Yongju Ahn, Kyudong Han","doi":"10.1007/s13258-024-01526-6","DOIUrl":"10.1007/s13258-024-01526-6","url":null,"abstract":"<p><strong>Background: </strong>Since most of the commonly known oral diseases are explained in link with balance of microbial community, an accurate bacterial taxonomy profiling for determining bacterial compositional network is essential. However, compared to intestinal microbiome, research data pool related to oral microbiome is small, and general 16S rRNA screening method has a taxonomy misclassification issue in confirming complex bacterial composition at the species level.</p><p><strong>Objective: </strong>Present study aimed to explore bacterial compositional networks at the species level within saliva of 39 oral disease patients (Dental Caries group: n = 26 and Periodontitis group: n = 13) through comparison with public Korean-specific healthy oral microbiome data.</p><p><strong>Methods: </strong>Here, we applied comprehensive molecular diagnostics based on qRT-PCR and Sanger sequencing methods to complement the technical limitations of NGS-based 16S V3-V4 amplicon sequencing technology.</p><p><strong>Results: </strong>As a result of microbiome profiling at the genus level, relative frequencies of many nitrate-reducing bacteria within each oral disease group were found to be significantly low compared to the healthy group. In addition, the molecular diagnostics-based bacterial identification method allowed the determination of the correct taxonomy of screened primary colonizers (Streptococcus and Actinomyces unclassification clusters) for each oral disease. Finally, as with the results of microbiome profiling at the genus level, many core-species classified within the saliva of each oral disease group were also related to nitrate-reduction, and it was estimated that various pathogens associated with each disease formed a bacterial network with the core-species.</p><p><strong>Conclusion: </strong>Our study introduced a novel approach that can compensate for the difficulty of identifying an accurate bacterial compositional network at the species level due to unclear taxonomy classification by using the convergent approach of NGS-molecular diagnostics. Ultimately, we suggest that our experimental approach and results could be potential reference materials for researchers who intend to prevent oral disease by determining the correlation between oral health and bacterial compositional network according to the changes in the relative frequency for nitrate-reducing species.</p>","PeriodicalId":12675,"journal":{"name":"Genes & genomics","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141283484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High-Resolution Melting (HRM) analysis of DNA methylation using semiconductor chip-based digital PCR.","authors":"Jinuk Jeong, Yongsu Yang, Min-Sik Song, Hee-Young Won, Andrew T Han, Songmi Kim","doi":"10.1007/s13258-024-01527-5","DOIUrl":"10.1007/s13258-024-01527-5","url":null,"abstract":"<p><strong>Background: </strong>Digital PCR (dPCR) technology allows absolute quantification and detection of disease-associated rare variants, and thus the use of dPCR technology has been increasing in clinical research and diagnostics. The high-resolution melting curve analysis (HRM) of qPCR is widely used to distinguish true positives from false positives and detect rare variants. In particular, qPCR-HRM is commonly used for methylation assessment in research and diagnostics due to its simplicity and high reproducibility. Most dPCR instruments have limited fluorescence channels available and separate heating and imaging systems. Therefore, it is difficult to perform HRM analysis using dPCR instruments.</p><p><strong>Objective: </strong>A new digital real-time PCR instrument (LOAA) has been recently developed to integrate partitioning, thermocycling, and imaging in a single dPCR instrument. In addition, a new technique to perform HRM analysis is utilized in LOAA. The aim of the present study is to evaluate the efficiency and accuracy of LOAA dPCR on HRM analysis for the detection of methylation.</p><p><strong>Methods: </strong>In this study, comprehensive comparison with Bio-Rad qRT-PCR and droplet-based dPCR equipment was performed to verify the HRM analysis-based methylation detection efficiency of the LOAA digital PCR equipment. Here, sodium bisulfite modification method was applied to detect methylated DNA sequences by each PCR method.</p><p><strong>Results: </strong>Melting curve analysis detected four different Tm values using LOAA and qPCR, and found that LOAA, unlike qPCR, successfully distinguished between different Tm values when the Tm values were very similar. In addition, melting temperatures increased by each methylation were about 0.5℃ for qPCR and about 0.2 ~ 0.6℃ for LOAA. The melting temperature analyses of methylated and unmethylated DNA samples were conducted using LOAA dPCR with TaqMan probes and EvaGreen, and the result found that Tm values of methylated DNA samples are higher than those of unmethylated DNA samples.</p><p><strong>Conclusion: </strong>The present study shows that LOAA dPCR could detect different melting temperatures according to methylation status of target sequences, indicating that LOAA dPCR would be useful for diagnostic applications that require the accurate quantification and assessment of DNA methylation.</p>","PeriodicalId":12675,"journal":{"name":"Genes & genomics","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141288009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transposable elements contribute to tissue-specific gene regulation in humans.","authors":"Arsala Ali, Ping Liang","doi":"10.1007/s13258-024-01550-6","DOIUrl":"https://doi.org/10.1007/s13258-024-01550-6","url":null,"abstract":"<p><strong>Background: </strong>Transposable elements (TEs) contribute to approximately half of the human genome, and along with many other functions, they have been known to play a role in gene regulation in the genome. With TEs' active/repressed states varying across tissue and cell types, they have the potential to regulate gene expression in a tissue-specific manner.</p><p><strong>Objective and methods: </strong>To provide a systematic analysis of TEs' contribution in tissue-specific gene regulation, we examined the regulatory elements and genes in association with TE-derived regulatory sequences in 14 human cell lines belonging to 10 different tissue types using the functional genomics data from the ENCODE project. Specifically, we separately analyzed regulatory regions identified by three different approaches (DNase hypersensitive sites (DHS), histone active sites (HA), and histone repressive sites (HR)).</p><p><strong>Results: </strong>These regulatory regions showed to be distinct from each other by sharing less than 2.5% among all three types and more than 95% showed to be cell line-specific. Despite a lower total TE content overall than the genome average, each regulatory sequence type showed enrichment for one or two specific TE type(s): DHS for long terminal repeats (LTRs) and DNA transposons, HA for short interspersed nucleotide elements (SINEs), and HR for LTRs. In contrast, SINE was shown to be overrepresented in all three types of regulatory sequences located in gene-neighboring regions. TE-regulated genes were mostly shown to have cell line specific pattern, and tissue-specific genes (TSGs) showed higher usage of TE regulatory sequences in the tissue of their expression. While TEs in the regulatory sequences showed to be older than their genome-wide counterparts, younger TEs were shown to be more likely used in cell line specific regulatory sequences.</p><p><strong>Conclusions: </strong>Collectively, our study provided further evidence enforcing an important contribution of TEs to tissue-specific gene regulation in humans.</p>","PeriodicalId":12675,"journal":{"name":"Genes & genomics","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141859516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification and expression analysis of nuclear factor Y transcription factor genes under drought, cold and Eldana infestation in sugarcane (Saccharum spp. hybrid).","authors":"Jancke le Roux, Robyn Jacob, Riëtte Fischer, Christell van der Vyver","doi":"10.1007/s13258-024-01529-3","DOIUrl":"10.1007/s13258-024-01529-3","url":null,"abstract":"<p><strong>Background: </strong>The Nuclear Factor Y (NF-Y) transcription factor (TF) gene family plays a crucial role in plant development and response to stress. Limited information is available on this gene family in sugarcane.</p><p><strong>Objectives: </strong>To identify sugarcane NF-Y genes through bioinformatic analysis and phylogenetic association and investigate the expression of these genes in response to abiotic and biotic stress.</p><p><strong>Methods: </strong>Sugarcane NF-Y genes were identified using comparative genomics from functionally annotated Poaceae and Arabidopsis species. Quantitative PCR and transcriptome analysis assigned preliminary functional roles to these genes in response to water deficit, cold and African sugarcane borer (Eldana saccharina) infestation.</p><p><strong>Results: </strong>We identify 21 NF-Y genes in sugarcane. Phylogenetic analysis revealed three main branches representing the subunits with potential discrepancies present in the assignment of numerical names of some NF-Y putative orthologs across the different species. Gene expression analysis indicated that three genes, ShNF-YA1, A3 and B3 were upregulated and two genes, NF-YA4 and A7 were downregulated, while three genes were upregulated, ShNF-YB2, B3 and C4, in the plants exposed to water deficit and cold stress, respectively. Functional involvement of NF-Y genes in the biotic stress response were also detected where three genes, ShNF-YA6, A3 and A7 were downregulated in the early resistant (cv. N33) response to Eldana infestation whilst only ShNF-YA6 was downregulated in the susceptible (cv. N11) early response.</p><p><strong>Conclusions: </strong>Our research findings establish a foundation for investigating the function of ShNF-Ys and offer candidate genes for stress-resistant breeding and improvement in sugarcane.</p>","PeriodicalId":12675,"journal":{"name":"Genes & genomics","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11329523/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141320835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular insights into TP53 mutation (p. Arg267Trp) and its connection to Choroid Plexus Carcinomas and Li-Fraumeni Syndrome.","authors":"Zainularifeen Abduljaleel","doi":"10.1007/s13258-024-01531-9","DOIUrl":"10.1007/s13258-024-01531-9","url":null,"abstract":"<p><strong>Background: </strong>Choroid plexus carcinomas (CPCs) are rare malignant tumors primarily affecting pediatric patients and often co-occur with Li-Fraumeni Syndrome (LFS), an inherited predisposition to early-onset malignancies in multiple organ systems. LFS is closely linked to TP53 mutations, with germline TP53 gene mutations present in approximately 75% of Li-Fraumeni syndrome families and 25% of Li-Fraumeni-like syndrome families. Individuals with TP53 mutations also have an elevated probability of carrying mutations in BRCA1 and BRCA2 genes.</p><p><strong>Objective: </strong>To investigate the structural and functional implications of the TP53: 799C > T, p. (Arg267Trp) missense mutation, initially identified in a Saudi family, and understand its impact on TP53 functionality and related intermolecular interactions.</p><p><strong>Methods: </strong>Computational analyses were conducted to examine the structural modifications resulting from the TP53: 799C > T, p. (Arg267Trp) mutation. These analyses focused on the mutation's impact on hydrogen bonding, ionic interactions, and the specific interaction with Cell Cycle and Apoptosis Regulator 2 (CCAR2), as annotated in UniProt.</p><p><strong>Results: </strong>The study revealed that the native Arg267 residue is critical for a salt bridge interaction with glutamic acid at position 258. The mutation-induced charge alteration has the potential to disrupt this ionic bonding. Additionally, the mutation is located within an amino acid region crucial for interaction with CCAR2. The altered properties of the amino acid within this domain may affect its functionality and disrupt this interaction, thereby impacting the regulation of catalytic enzyme activity.</p><p><strong>Conclusions: </strong>Our findings highlight the intricate intermolecular interactions governing TP53 functionality. The TP53: 799C > T, p. (Arg267Trp) mutation causes structural modifications that potentially disrupt critical ionic bonds and protein interactions, offering valuable insights for the development of targeted mutants with distinct functional attributes. These insights could inform therapeutic strategies for conditions associated with TP53 mutations.</p>","PeriodicalId":12675,"journal":{"name":"Genes & genomics","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141418542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic regulation of HERVs: Implications for cancer immunotherapy.","authors":"Joo Mi Yi","doi":"10.1007/s13258-024-01546-2","DOIUrl":"https://doi.org/10.1007/s13258-024-01546-2","url":null,"abstract":"<p><strong>Background: </strong>Human endogenous retroviruses (HERVs), integrated into the human genome during primate evolution, constitute approximately 8% of the human genome. Although most HERVs are non-protein-coding owing to mutations, insertions, deletions, and truncations, recent research has revealed their diverse roles in biological processes, including disease pathogenesis.</p><p><strong>Objective: </strong>Although many HERVs remain inactive, they have been implicated in various diseases, particularly cancer, prompting an increased interest in harnessing HERVs for therapeutic purposes. This review explores the recent advancements in our understanding of the biological roles of HERVs, emphasizing their clinical relevance in cancer treatment.</p><p><strong>Methods: </strong>Here, we discuss how the detection of transposable elements (TEs), including HERVs, by the immune system triggers innate immune responses in human cancers.</p><p><strong>Conclusion: </strong>Additionally, we outline recent progress in elucidating the implications of HERV activation in cancer and how targeting HERVs holds promise for anti-cancer treatments by modulating epigenetic plasticity and disrupting cancer initiation and progression.</p>","PeriodicalId":12675,"journal":{"name":"Genes & genomics","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141859515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Particulate matter-induced gene expression patterns in human-derived cells based on 11 public gene expression datasets.","authors":"Sanghyun Roh, Jeongeun Hwang, Joo-Hoo Park, Dae Jin Song, Jeong-An Gim","doi":"10.1007/s13258-024-01512-y","DOIUrl":"10.1007/s13258-024-01512-y","url":null,"abstract":"<p><strong>Background: </strong>Exposure to particulate matter (PM) and house dust mite (HDM) can change the expression patterns of inflammation-, oxidative stress-, and cell death-related genes. We investigated the changes in gene expression patterns owing to PM exposure.</p><p><strong>Objective: </strong>This study examined the changes in gene expression patterns following PM exposure.</p><p><strong>Methods: </strong>We searched for differentially expressed genes (DEGs) following PM exposure using five cell line-based RNA-seq or microarray datasets and six human-derived datasets. The enrichment terms of the DEGs were assessed.</p><p><strong>Results: </strong>DEG analysis yielded two gene sets. Thus, enrichment analysis was performed for each gene set, and the enrichment terms related to respiratory diseases were presented. The intersection of six human-derived datasets and two gene sets was obtained, and the expression patterns following PM exposure were observed.</p><p><strong>Conclusions: </strong>Two gene sets were obtained for cells treated with PM and their expression patterns were presented following verification in human-derived cells. Our findings suggest that exposure to PM_2.5 and HDM may reveal changes in genes that are associated with diseases, such as allergies, highlighting the importance of mitigating PM_2.5 and HDM exposure for disease prevention.</p>","PeriodicalId":12675,"journal":{"name":"Genes & genomics","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140908536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A study on construction of a prognosis model for liver cancer based on analgesic targets and screening therapeutic drugs.","authors":"Xueyan Jiang, Yaodong Ping, Yuan Chen, Benben Zhu, Rong Fu, Yiwei Hao, Lei Fan","doi":"10.1007/s13258-024-01515-9","DOIUrl":"10.1007/s13258-024-01515-9","url":null,"abstract":"<p><strong>Background: </strong>Liver cancer is one of the most malignant liver diseases in the world, and the 5-year survival rate of such patients is low. Analgesics are often used to cure pain prevalent in liver cancer. The expression changes and clinical significance of the analgesic targets (ATs) in liver cancer have not been deeply understood.</p><p><strong>Objective: </strong>The purpose of this study is to clarify the expression pattern of ATs gene in liver cancer and its clinical significance. Through the comprehensive analysis of transcriptome data and clinical parameters, the prognosis model related to ATs gene is established, and the drug information sensitive to ATs is mined.</p><p><strong>Methods: </strong>The study primarily utilized transcriptomic data and clinical information from liver cancer patients sourced from The Cancer Genome Atlas (TCGA) database. These data were employed to analyze the expression of ATs, conduct survival analysis, gene set variation analysis (GSVA), immune cell infiltration analysis, establish a prognostic model, and perform other bioinformatic analyses. Additionally, data from liver cancer patients in the International Cancer Genome Consortium (ICGC) were utilized to validate the accuracy of the model. Furthermore, the impact of analgesics on key genes in the prognostic model was assessed using data from the Comparative Toxicogenomics Database (CTD).</p><p><strong>Results: </strong>The study investigated the differential expression of 58 ATs genes in liver cancer compared to normal tissues. Patients were stratified based on ATs expression, revealing varied survival outcomes. Functional enrichment analysis highlighted distinctions in spindle organization, centrosome, and spindle microtubule functions. Prognostic modeling identified low TP53 expression as protective, while elevated CCNA2, NEU1, and HTR2C levels posed risks. Commonly used analgesics, including acetaminophen and others, were found to influence the expression of these genes. These findings provide insights into potential therapeutic strategies for liver cancer and shed light on the molecular mechanisms underlying its progression.</p><p><strong>Conclusions: </strong>The collective analysis of gene signatures associated with ATs suggests their potential as prognostic predictors in hepatocellular carcinoma patients. These findings not only offer insights into cancer therapy but also provide novel avenues for the development of indications for analgesics.</p>","PeriodicalId":12675,"journal":{"name":"Genes & genomics","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141161795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"STAT3 phosphorylation at Tyr705 affects DRP1 (dynamin-related protein 1) controlled-mitochondrial fission during the development of apoptotic-resistance in pulmonary arterial endothelial cells.","authors":"Han Zhang, Li Chen, Jiachen Li, Jiashu Sun, Qixu Zhao, Sheng Wang, Gang Li","doi":"10.1007/s13258-024-01522-w","DOIUrl":"10.1007/s13258-024-01522-w","url":null,"abstract":"<p><strong>Background: </strong>The apoptosis-resistant pulmonary arterial endothelial cells (PAECs) are known to be major players in the pulmonary remodeling of pulmonary arterial hypertension (PAH) and exhibit an abnormal metabolic profile with mitochondrial dysfunction. Mitochondrial fission has been shown to regulate the apoptosis of several cell types, but this is largely unexplored in the PAECs.</p><p><strong>Objective: </strong>The roles of mitochondrial fission control by Dynamin related protein-1 (DRP1) in the development of PAECs apoptosis suppression were investigated in present study and the potential mechanisms behind this were furtherly explored.</p><p><strong>Methods: </strong>The mitochondrial morphology was investigated in PAECs from PAH rats with the pulmonary plexiform lesions, and the relations of it with DRP1 expression and apoptosis were furtherly identified in apoptosis-resistant PAECs induced by hypoxia. PAECs were isolated from rats with severe PAH and from normal subjects, the apoptotic-resistant PAECs were induced by hypoxia. DRP1 gene knockdown was achieved via DRP1-siRNA, DRP1 and STAT3 phosphorylation were blocked using its inhibitors, respectively. Apoptosis was analyzed by flow cytometry, and mitochondrial morphology was investigated by transmission electron microscope and confocal microscopy.</p><p><strong>Results: </strong>The PAECs isolated from PAH rats with the pulmonary plexiform-like lesions and displayed lower apoptotic rate with increased DRP1 expression and mitochondrial fragmentation. In addition, similar observations were achieved in apoptosis-resistant PAECs induced by hypoxia. Targeting DRP1 using siRNA and pharmacologic blockade prevented the mitochondrial fission and subsequent apoptotic resistance in PAECs under hypoxia. Mechanistically, STAT3 phosphorylation at Tyr705 was shown to be activated in both PAH and hypoxia-treated PAECs, leading to the regulation of DRP1 expression. Of importance, targeting STAT3Tyr705 phosphorylation prevented DRP1 disruption on apoptosis in PAECs under hypoxia.</p><p><strong>Conclusions: </strong>These data indicated that STAT3 phosphorylation at Tyr705 impacted DRP1-controlled mitochondrial fission during the development of apoptosis-resistance in PAECs, suggesting mitochondrial dynamics may represent a therapeutic target for PAH.</p>","PeriodicalId":12675,"journal":{"name":"Genes & genomics","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11208226/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140908541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}