Cellular and Molecular Life Sciences最新文献

{"title":"Mechanism of miR-130b-3p in relieving airway inflammation in asthma through HMGB1-TLR4-DRP1 axis.","authors":"Xue Han, Yilan Song, Yihua Piao, Zhiguang Wang, Yan Li, Qingsong Cui, Hongmei Piao, Guanghai Yan","doi":"10.1007/s00018-024-05529-0","DOIUrl":"10.1007/s00018-024-05529-0","url":null,"abstract":"<p><p>Asthma is a chronic inflammatory respiratory disease characterized by recurrent breathing difficulties caused by airway obstruction and hypersensitivity. Although there is diversity in their specific mechanisms, microRNAs (miRNAs) have a significant impact on the development of asthma. Currently, the contribution of miR-130b-3p to asthma remains elusive. The goal of this study was to examine whether miR-130b-3p attenuates house dust mite (HDM)-induced asthma through High-mobility group box protein 1 (HMGB1)/Toll-like receptor 4 (TLR4)/mitochondrial fission protein (DRP1) signaling pathway. We elucidate that miR-130b-3p can bind to the HMGB1 3'UTR, attenuating HMGB1 mRNA and protein levels, and nucleo-cytoplasmic translocation of HMGB1. We observed that miR-130b-3p agomir or HMGB1 CKO attenuated HDM-induced airway inflammation and hyperresponsiveness, and decreased Th2-type cytokines in bronchoalveolar lavage fluid (BALF) and mediastinal lymph nodes. Further, HMGB1 CKO contributes to alleviating Th2 inflammation in AT-II cells (CD45.2^-/CD31^-/Epcam^-+/proSP-C⁺/MHC-II⁺) from lung single cell suspensions of asthmatic mice by flow cytometry. Our findings identified miR-130b-3p as a potent regulator in asthma that exerts its anti-inflammatory effects by targeting HMGB1 and the subsequent HMGB1/TLR4/DRP1axis, presenting a prospective novel therapeutic avenue for asthma management.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"9"},"PeriodicalIF":6.2,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11662128/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ENPP1/CD203a-targeting heavy-chain antibody reveals cell-specific expression on human immune cells.","authors":"Hannah Lorenz, Stephan Menzel, Nataliia Roshchyna, Birte Albrecht, Anna Josephine Gebhardt, Enja Schneider, Friedrich Haag, Björn Rissiek, Ralf Oheim, Friedrich Koch-Nolte, Riekje Winzer, Eva Tolosa","doi":"10.1007/s00018-024-05539-y","DOIUrl":"10.1007/s00018-024-05539-y","url":null,"abstract":"<p><p>ENPP1/CD203a is a membrane-bound ectonucleotidase capable of hydrolyzing ATP, cGAMP and other substrates. Its enzymatic activity plays an important role in the balance of extracellular adenine nucleotides and the modulation of purinergic signaling, in soft tissue calcification, and in the regulation of the cGAS/STING pathway. However, a detailed analysis of ENPP1 surface expression on human immune cells has not been performed. Here, we selected VHH domains from human ENPP1-immunized alpacas to generate heavy-chain antibodies targeting ENPP1, and analyzed cell surface expression on all circulating immune cell subsets using flow cytometry. We find high expression of ENPP1 in CD141^high conventional dendritic cells (cDC1), while ENPP1 was not detectable on other dendritic cells and monocytes. In the lymphocytic compartment, only CD56^bright natural killer cells and mucosal-associated invariant T cells (MAIT) express ENPP1. In contrast, all other T cell subpopulations, CD56^dim natural killer cells and B lymphocytes do not or only minimally express ENPP1. In summary, we describe highly cell type-specific expression of ENPP1 in the immune system using a newly generated heavy-chain antibody. This reagent will help to decipher the function of ENPP1 in the regulation of the immune response, allow a quick identification of ENPP1-deficiency and of ENPP1-positive tumors, and constitutes the basis for targeted anti-tumor intervention.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"6"},"PeriodicalIF":6.2,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11655721/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142851902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DNMT1 prolonged absence is a tunable cellular stress that triggers cell proliferation arrest to protect from major DNA methylation loss.","authors":"Salvatore Martino, Serena Gargano, Pietro Salvatore Carollo, Aldo Di Leonardo, Viviana Barra","doi":"10.1007/s00018-024-05547-y","DOIUrl":"10.1007/s00018-024-05547-y","url":null,"abstract":"<p><p>Methylation of cytosine in CpG dinucleotides is an epigenetic modification carried out by DNA-methyltransferases (DNMTs) that contributes to chromatin condensation and structure and, thus, to gene transcription regulation and chromosome stability. DNMT1 maintains the DNA methylation pattern of the genome at each cell cycle by copying it to the newly synthesized DNA strand during the S-phase. DNMT1 pharmacological inhibition as well as genetic knockout and knockdown, leads to passive DNA methylation loss. However, these strategies have been associated with different cell fates, even in the same cell background, suggesting that they can question the interpretation of the obtained results. Using a cell system in which endogenous DNMT1 is fused with an inducible degron and can be rapidly degraded, we found that in non-tumoral RPE-1 cells, DNMT1 loss progressively induced cell proliferation slowing-down and cell cycle arrest at the G1/S transition. The latter is due to p21 activation, which is partly mediated by p53 and leads to a global reduction in DNA methylation. DNMT1 restoration rescues cell proliferation, indicating that its deregulation is sensed as tunable cellular stress.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"7"},"PeriodicalIF":6.2,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11655745/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Required minimal protein domain of flower for synaptobrevin2 endocytosis in cytotoxic T cells.","authors":"Keerthana Ravichandran, Claudia Schirra, Katja Urbansky, Szu-Min Tu, Nadia Alawar, Stefanie Mannebach, Elmar Krause, David Stevens, C Roy D Lancaster, Veit Flockerzi, Jens Rettig, Hsin-Fang Chang, Ute Becherer","doi":"10.1007/s00018-024-05528-1","DOIUrl":"10.1007/s00018-024-05528-1","url":null,"abstract":"<p><p>Flower, a highly conserved protein, crucial for endocytosis and cellular fitness, has been implicated in cytotoxic T lymphocyte (CTL) killing efficiency through its role in cytotoxic granule (CG) endocytosis at the immune synapse (IS). This study explores the molecular cues that govern Flower-mediated CG endocytosis by analyzing uptake of Synaptobrevin2, a protein specific to CG in mouse CTL. Using immunogold electron microscopy and total internal fluorescence microscopy, we found that Flower translocates in a stimulus-dependent manner from small vesicles to the IS, thereby ensuring specificity in CG membrane protein recycling. Using confocal live-cell imaging, we assessed the ability of a range of naturally occurring mouse, human and Drosophila isoforms to rescue defective endocytosis in Flower KO CTLs. This analysis demonstrated that the N-terminal portion of the protein, encompassing amino acids 1-106 in mice, is the minimal domain necessary for Synaptobrevin2 endocytosis. Additionally, we identified two pivotal sites through site-specific mutation: a putative AP2-binding site, and a tyrosine at position 104 in mouse Flower. These findings provide insights into Flower's specific functional domain essential for CG endocytosis, which is a key process in mediating T cell serial killing required for the effective fight against cancer.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"8"},"PeriodicalIF":6.2,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11655906/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142852923","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lysine and arginine methylation of transcription factors.","authors":"Benedetto Daniele Giaimo, Francesca Ferrante, Tilman Borggrefe","doi":"10.1007/s00018-024-05531-6","DOIUrl":"10.1007/s00018-024-05531-6","url":null,"abstract":"<p><p>Post-translational modifications (PTMs) are implicated in many biological processes including receptor activation, signal transduction, transcriptional regulation and protein turnover. Lysine's side chain is particularly notable, as it can undergo methylation, acetylation, SUMOylation and ubiquitination. Methylation affects not only lysine but also arginine residues, both of which are implicated in epigenetic regulation. Beyond histone-tails as substrates, dynamic methylation of transcription factors has been described. The focus of this review is on these non-histone substrates providing a detailed discussion of what is currently known about methylation of hypoxia-inducible factor (HIF), P53, nuclear receptors (NRs) and RELA. The role of methylation in regulating protein stability and function by acting as docking sites for methyl-reader proteins and via their crosstalk with other PTMs is explored.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"5"},"PeriodicalIF":6.2,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11649617/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phosphocholine inhibits proliferation and reduces stemness of endometrial cancer cells by downregulating mTOR-c-Myc signaling.","authors":"Kunxiang Gong, Yanqin Zheng, Yaqiong Liu, Tiansong Zhang, Yiming Song, Weiwei Chen, Lirong Guo, Jie Zhou, Wenjie Liu, Tianlin Fang, Yun Chen, Jingyao Wang, Feifei Pan, Kun Shi","doi":"10.1007/s00018-024-05517-4","DOIUrl":"10.1007/s00018-024-05517-4","url":null,"abstract":"<p><strong>Background: </strong>Endometrial cancer (EC) represents a serious health concern among women globally. Excessive activation of the protooncogene c-Myc (c-Myc) is associated with the proliferation and stemness of EC cells. Phosphocholine (PC), which is synthesized by choline kinase alpha (CHKA) catalysis, is upregulated in EC tumor tissues. The present study aimed to investigate the effect of PC accumulation on EC cells and clarify the relationship between PC accumulation and c-Myc activity in EC.</p><p><strong>Methods: </strong>The c-Myc and CHKA expression in EC tumor tissues were examined using immunohistochemistry. Cell Counting Kit-8 assay, colony formation assay, flow cytometry, western blotting, BrdU staining, and tumorsphere formation assay were used to assess the effect of PC accumulation on EC cells. The mechanism by which PC accumulation inhibits c-Myc was evaluated using RNA-sequencing. Patient-derived organoid (PDO) models were utilised to explore the preclinical efficacy of PC against EC cells.</p><p><strong>Results: </strong>PC accumulation suppressed EC cell proliferation and stemness by inhibiting the activation of the mammalian target of rapamycin (mTOR)-c-Myc signaling. PC accumulation promoted excessive reactive oxygen species production, which reduced the expression of GTPase HRAS. This, in turn, inhibited the mTOR-c-Myc axis and induced EC cell apoptosis. Finally, PC impeded proliferation and downregulated the expression of the mTOR-MYC signaling in EC PDO models.</p><p><strong>Conclusions: </strong>PC accumulation impairs the proliferation ability and stem cell characteristics of EC cells by inhibiting the activated mTOR-c-Myc axis, potentially offering a promising strategy to enhance the efficacy of EC clinical therapy through the promotion of PC accumulation in tumor cells.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"3"},"PeriodicalIF":6.2,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11649893/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Golgi pH elevation due to loss of V-ATPase subunit V0a2 function correlates with tissue-specific glycosylation changes and globozoospermia.","authors":"Johannes Kopp, Denise Jahn, Guido Vogt, Anthi Psoma, Edoardo Ratto, Willy Morelle, Nina Stelzer, Ingrid Hausser, Anne Hoffmann, Miguel Rodriguez de Los Santos, Leonard A Koch, Björn Fischer-Zirnsak, Christian Thiel, Wilhelm Palm, David Meierhofer, Geert van den Bogaart, François Foulquier, Andreas Meinhardt, Uwe Kornak","doi":"10.1007/s00018-024-05506-7","DOIUrl":"10.1007/s00018-024-05506-7","url":null,"abstract":"<p><p>Loss-of-function variants in ATP6V0A2, encoding the trans Golgi V-ATPase subunit V0a2, cause wrinkly skin syndrome (WSS), a connective tissue disorder with glycosylation defects and aberrant cortical neuron migration. We used knock-out (Atp6v0a2^-/-) and knock-in (Atp6v0a2^RQ/RQ) mice harboring the R755Q missense mutation selectively abolishing V0a2-mediated proton transport to investigate the WSS pathomechanism. Homozygous mutants from both strains displayed a reduction of growth, dermis thickness, and elastic fiber formation compatible with WSS. A hitherto unrecognized male infertility due to globozoospermia was evident in both mouse lines with impaired Golgi-derived acrosome formation and abolished mucin-type O-glycosylation in spermatids. Atp6v0a2^-/- mutants showed enhanced fucosylation and glycosaminoglycan modification, but reduced levels of glycanated decorin and sialylation in skin and/or fibroblasts, which were absent or milder in Atp6v0a2^RQ/RQ. Atp6v0a2^RQ/RQ mutants displayed more abnormal migration of cortical neurons, correlating with seizures and a reduced O-mannosylation of α-dystroglycan. While anterograde transport within the secretory pathway was similarly delayed in both mutants the brefeldin A-induced retrograde fusion of Golgi membranes with the endoplasmic reticulum was less impaired in Atp6v0a2^RQ/RQ. Measurement of the pH in the trans Golgi compartment revealed a shift from 5.80 in wildtype to 6.52 in Atp6v0a2^-/- and 6.25 in Atp6v0a2^RQ/RQ. Our findings suggest that altered O-glycosylation is more relevant for the WSS pathomechanism than N-glycosylation and leads to a secondary dystroglycanopathy. Most phenotypic and cellular properties correlate with the different degrees of trans Golgi pH elevation in both mutants underlining the fundamental relevance of pH regulation in the secretory pathway.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"4"},"PeriodicalIF":6.2,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11649611/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptome and epigenome dynamics of the clonal heterogeneity of human induced pluripotent stem cells for cardiac differentiation.","authors":"Jihye Yun, Jaemin So, Seunghee Jeong, Jiye Jang, Soyoung Han, Junseok Jeon, Kyungho Lee, Hye Ryoun Jang, Jaecheol Lee","doi":"10.1007/s00018-024-05493-9","DOIUrl":"10.1007/s00018-024-05493-9","url":null,"abstract":"<p><p>Human induced pluripotent stem cells (hiPSCs) generate multiple clones with inherent heterogeneity, leading to variations in their differentiation capacity. Previous studies have primarily addressed line-to-line variations in differentiation capacity, leaving a gap in the comprehensive understanding of clonal heterogeneity. Here, we aimed to profile the heterogeneity of hiPSC clones and identify predictive biomarkers for cardiomyocyte (CM) differentiation capacity by integrating transcriptomic, epigenomic, endogenous retroelement, and protein kinase phosphorylation profiles. We generated multiple clones from a single donor and validated that these clones exhibited comparable levels of pluripotency markers. The clones were classified into two groups based on their differentiation efficiency to CMs-productive clone (PC) and non-productive clone (NPC). We performed RNA sequencing (RNA-seq) and assay for transposase-accessible chromatin with sequencing (ATAC-seq). NPC was enriched in vasculogenesis and cell adhesion, accompanied by elevated levels of phosphorylated ERK1/2. Conversely, PC exhibited enrichment in embryonic organ development and transcription factor activation, accompanied by increased chromatin accessibility near transcription start site (TSS) regions. Integrative analysis of RNA-seq and ATAC-seq revealed 14 candidate genes correlated with cardiac differentiation potential. Notably, TEK and SDR42E1 were upregulated in NPC. Our integrative profiles enhance the understanding of clonal heterogeneity and highlight two novel biomarkers associated with CM differentiation. This insight may facilitate the identification of suboptimal hiPSC clones, thereby mitigating adverse outcomes in clinical applications.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"2"},"PeriodicalIF":6.2,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11635083/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142806178","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cross-regulation of RNA methylation modifications and R-loops: from molecular mechanisms to clinical implications.","authors":"Yuqing Wu, Shen Lin, Hong Chen, Xiangyi Zheng","doi":"10.1007/s00018-024-05536-1","DOIUrl":"10.1007/s00018-024-05536-1","url":null,"abstract":"<p><p>R-loops, RNA-DNA hybrid structures, are integral to key cellular processes such as transcriptional regulation, DNA replication, and repair. However, aberrant accumulation of R-loops can compromise genomic integrity, leading to the development of various diseases. Emerging evidence underscores the pivotal role of RNA methylation modifications, particularly N6-methyladenosine (m⁶A) and 5-methylcytosine (m⁵C), in orchestrating the formation, resolution, and stabilization of R-loops. These modifications dynamically regulate R-loop metabolism, exerting bidirectional control by either facilitating or resolving R-loop structures during gene expression regulation and DNA damage repair. Dysregulation of RNA methylation and the resultant imbalance in R-loop homeostasis are closely linked to the pathogenesis of diseases such as cancer and neurodegenerative disorders. Thus, deciphering the cross-talk between RNA methylation and R-loops is essential for understanding the mechanisms underlying genomic stability and identifying novel therapeutic targets. This review provides a comprehensive analysis of the role of RNA methylation in R-loop dynamics, examines their physiological and pathological implications, and proposes future directions for therapeutic intervention targeting these processes.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"1"},"PeriodicalIF":6.2,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11631829/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799618","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic regulation of mitochondrial fission and cardiac fibrosis via sFRP3 promoter methylation.","authors":"Shun-Xiang Jiang, Ze-Yu Zhou, Bin Tu, Kai Song, Li-Chan Lin, Zhi-Yan Liu, Wei Cao, Jian-Yuan Zhao, Hui Tao","doi":"10.1007/s00018-024-05516-5","DOIUrl":"10.1007/s00018-024-05516-5","url":null,"abstract":"<p><p>In the process of cardiac fibrosis, the balance between the Wnt/β-catenin signalling pathway and Wnt inhibitory factor genes plays an important role. Secreted frizzled-related protein 3 (sFRP3), a Wnt inhibitory factor, has been linked to epigenetic mechanisms. However, the underlying role of epigenetic regulation of sFRP3, which is crucial in fibroblast proliferation and migration, in cardiac fibrosis have not been elucidated. Therefore, we aimed to investigate epigenetic and transcription of sFRP3 in cardiac fibrosis. Using clinical samples and animal models, we investigated the role of sFRP3 promoter methylation in potentially enhancing cardiac fibrosis. We also attempted to characterize the underlying mechanisms using an isoprenaline-induced cardiac fibrosis mouse model and cultured primary cardiac fibroblasts. Hypermethylation of sFRP3 was associated with perpetuation of fibroblast activation and cardiac fibrosis. Additionally, mitochondrial fission, regulated by the Drp1 protein, was found to be significantly altered in fibrotic hearts, contributing to fibroblast proliferation and cardiac fibrosis. Epigenetic modification of sFRP3 promoter methylation also influenced mitochondrial dynamics, linking sFRP3 repression to excessive mitochondrial fission. Moreover, sFRP3 hypermethylation was mediated by DNA methyltransferase 3A (DNMT3A) in cardiac fibrosis and fibroblasts, and DNMT3A knockdown demethylated the sFRP3 promoter, rescued sFRP3 loss, and ameliorated the isoprenaline-induced cardiac fibrosis and cardiac fibroblast proliferation, migration and mitochondrial fission. Mechanistically, DNMT3A was shown to epigenetically repress sFRP3 expression via promoter methylation. We describe a novel epigenetic mechanism wherein DNMT3A represses sFRP3 through promoter methylation, which is a critical mediator of cardiac fibrosis and mitochondrial fission. Our findings provide new insights for the development of preventive measures for cardiac fibrosis.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"81 1","pages":"483"},"PeriodicalIF":6.2,"publicationDate":"2024-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11625034/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142791241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}