Journal of Biological Chemistry最新文献

{"title":"Specific phosphoinositide interaction of Jps1 is a key feature during unconventional secretion in Ustilago maydis.","authors":"Sanchi Dali,Michèle Schultz,Marian Köster,Michael Kamel,Max Busch,Wieland Steinchen,Sebastian Hänsch,Athanasios Papadopoulos,Jens Reiners,Sander H J Smits,Alexej Kedrov,Florian Altegoer,Kerstin Schipper","doi":"10.1016/j.jbc.2025.110215","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110215","url":null,"abstract":"Protein secretion is indispensable for essential cellular processes in eukaryotic cells, contributing significantly to nutrient acquisition, defense or communication. Alternative pathways bypassing the endomembrane system collectively referred to as unconventional secretion are gaining increasing attention. A number of important molecules such as cytokines, fibroblast growth factor or viral proteins are being exported through these mechanistically diverse pathways. In the fungal model Ustilago maydis, cytokinesis-dependent unconventional secretion mediates export of the chitinase Cts1 via the fragmentation zone. This membrane-rich compartment is formed between mother and daughter cells during cytokinesis. Recently, we identified Jps1, a previously uncharacterized protein, as a crucial factor for Cts1 localization and export. Combining biochemical experiments and in vivo studies, we here uncover two pivotal features of Jps1: dimerization and phosphoinositide (PIP) binding. Our findings reveal that a conserved structural core domain mediates homodimerization, while surrounding flexible variable regions suggest potential diversification in different basidiomycete species. Jps1 does not harbor a canonical PIP-binding domain but instead specificity of the interaction with the preferred PIP PI(4,5)P2 is determined by basic residues. Importantly, loss of PI(4,5)P2 binding specificity results in mislocalisation, morphological defects and reduced extracellular Cts1 activity, particularly at low cell densities. Our discoveries shed light on previously unknown key features of Jps1 and represents a crucial step towards understanding the broader implications of unconventional secretion in eukaryotic cells.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"230 1","pages":"110215"},"PeriodicalIF":4.8,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143932956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CRISPRi Screen Uncovers lncRNA Regulators of Human Monocyte Growth.","authors":"Cristina Flores-Arena, Eric Malekos, Christy Montano, Sergio Covarrubias, Lisa Sudek, Valory Dempsey, Vuky Huynh, Sol Katzman, Susan Carpenter","doi":"10.1016/j.jbc.2025.110204","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110204","url":null,"abstract":"<p><p>Long noncoding RNAs are emerging as critical regulators of biological processes. While there are over 36,000 lncRNAs annotated in the human genome we do not know the function for the majority. Here we performed a high-throughput CRISPRi screen to identify those lncRNAs that are important in viability in human monocytes using the cell line THP1. We identified a total of 38 hits from the screen and validated and characterized two of the top intergenic hits. The first is a lncRNA neighboring the macrophage viability transcription factor IRF8 (RP11-542M13.2 hereafter referred to as long noncoding RNA regulator of monocyte proliferation, LNCRMP) and the second is a lncRNA called OLMALINC (oligodendrocyte maturation-associated long intervening non-coding RNA) that was previously found to be important in oligodendrocyte maturation. Transcriptional repression of LNCRMP and OLMALINC from monocytes severely limited their proliferation capabilities. RNA-seq analysis of knockdown lines showed that LNCRMP regulated proapoptotic pathways while knockdown of OLMALINC impacted genes associated with the cell cycle. Data supports both LNCRMP and OLMALINC functioning in cis to regulate their neighboring proteins that are also essential for THP1 cell growth. This research highlights the importance of high-throughput screening as a powerful tool for quickly discovering functional long non-coding RNAs (lncRNAs) that play a vital role in regulating monocyte viability.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"110204"},"PeriodicalIF":4.0,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144002296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of a two-component kinase that initiates the bacterial catabolism of hydroxyphenylethanones.","authors":"Gara N Dexter,Jason C Grigg,Michael Zahn,Eloisa J Wheatley,Jennifer Lian,William W Mohn,Lindsay D Eltis","doi":"10.1016/j.jbc.2025.110210","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110210","url":null,"abstract":"The prodigious ability of bacteria to catabolize aromatic compounds has sparked considerable efforts to engineer bacteria to valorize lignin, an under-utilized component of biomass. Despite decades of study, key catabolic pathways and enzymes remain poorly characterized. We recently identified the hydroxyphenylethanone (Hpe) pathway, which enables Rhodococcus rhodochrous GD02 and other bacteria to catabolize 4-hydroxyacetophenone (HAP) and acetovanillone (AV), which are generated in the catalytic fractionation of lignin. Catabolism is initiated by a two-component, ATP-dependent dikinase, HpeHI, homologs of which are involved in the catabolism of other aromatic compounds. In biochemical studies, the kinase activity of HpeHI was highest at low ionic strength and low concentrations of Mn2+. HpeHI had highest apparent specificity for HAP and AV (kcat/KM ≥ 250 mM-1 s-1) and had submicromolar KM values for these substrates, consistent with the enzyme acting as a scavenging system. The enzyme also transformed 4-hydroxybenzaldehyde, vanillin, acetosyringone, and phenol. A 1.8 Å crystal structure of HpeI revealed that it is homologous to the ATP-grasp domain of rifampin phosphotransferase (RPH) while an AlphaFold model of HpeH indicated that it is homologous to the swivel and rifampin-binding domains of RPH. Consistent with HpeHI using a similar mechanism where the swivel domain transits between the spatially distinct substrate-binding sites, substitution of the conserved His residue in HpeH abolished kinase activity. Moreover, the HpeH component alone catalyzed phosphotransfer from 4-phosphoacetophenone to AV. This study reveals a subfamily of small molecule dikinases that comprise two components, some of which are involved in aromatic compound catabolism.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"16 1","pages":"110210"},"PeriodicalIF":4.8,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143932534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Covalent Binding of Thioredoxin to TXNIP is Required for Diet-induced Insulin Resistance in the Liver.","authors":"Sezin Dagdeviren,Megan F Hoang,Jialu Wang,Tamara Goldberger,Amelia M Yu,Steven J Blair,Jake C Benoit,Elisabeth M Ricci-Blair,Veronika Y Melnik,Bo-Yeon Kim,Lauren A Tauer,Julia-Josefine Scholz,Anna Worthmann,Christian Schlein,Deborah Stone,Natalie T Deuitch,Ivona Aksentijevich,Oskar Schnappauf,Jessica L Whited,Jason K Kim,Richard T Lee","doi":"10.1016/j.jbc.2025.110214","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110214","url":null,"abstract":"Hepatic insulin resistance is an important pathophysiology in type 2 diabetes, and the mechanisms by which high-caloric diets induce insulin resistance are unclear. Among vertebrate animals, mammals have retained a unique molecular change that allows an intracellular arrestin domain-containing protein called Thioredoxin-Interacting Protein (TXNIP) to bind covalently to thioredoxin, allowing TXNIP to \"sense\" oxidative stress(1). Here, we show that a single cysteine in TXNIP mediates the development of hepatic insulin resistance in the setting of a high-fat diet (HFD). Mice with an exchange of TXNIP Cysteine 247 for Serine (C247S) showed improved whole-body and hepatic insulin sensitivity compared to wild-type (WT) controls following an 8-week HFD. HFD-fed TXNIP C247S mouse livers also showed improved insulin signaling. The Transmembrane 7 superfamily member 2 (Tm7sf2) gene encodes for a sterol reductase involved in the process of cholesterol biosynthesis (2). We identified TM7SF2 as a potential mediator of enhanced insulin signaling in HFD-fed TXNIP C247S mouse livers. TM7SF2 increased Akt phosphorylation and suppressed gluconeogenic markers PCK1 and G6Pc specifically under oxidative-stress-induced conditions in HepG2 cells. We also present data suggesting that a heterozygous variant of TXNIP C247 is well-tolerated in humans. Thus, mammals have a single redox-sensitive amino acid in TXNIP that mediates insulin resistance in the setting of a HFD. Our results reveal an evolutionarily conserved mechanism for hepatic insulin resistance in obesity.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"12 1","pages":"110214"},"PeriodicalIF":4.8,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143932531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Parkin mediates the mitochondrial dysfunction through mRpL18.","authors":"Xiuxiu Ti,Hui Zuo,Guochun Zhao,Yuwei Li,Minghui Du,Liwen Xu,Shengnan Li,Zhaoliang Shan,Yuxue Gao,Guangming Gan,Yan Wang,Qing Zhang","doi":"10.1016/j.jbc.2025.110208","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110208","url":null,"abstract":"Loss of function of parkin leads to the mitochondrial dysfunction, which is closely related to Parkinson's disease. However, the in vivo mechanism is far from clear. One of the dogmas is that impaired Parkin causes dysfunction of mitophagy mediated by Pink1-Parkin axis. The other is that impaired Parkin causes Mfn accumulation which leads to mitochondrial dysfunction. Surprisingly, in Drosophila muscles, as reported, the first dogma is not applicable; for the second dogma, our study suggests that Parkin mediates the mitochondrial dysfunction through modulating mitochondrial morphology, which is determined by synergy of both Marf and mitochondrial protein mRpL18 got from our genome-wide screen, whose RNAi rescues parkin RNAi phenotype. Mechanistically, we found that impaired Parkin upregulated both the transcription and protein levels of mRpL18 dependent on its E3 ligase activity, causing the mRpL18 accumulation outside mitochondria. Consequently, cytosolic accumulated mRpL18 competitively bound Drp1, leading to the reduction of the binding of Drp1 to its receptor Fis1, which finally inhibited the mitochondrial fission and tipped the balance to mitochondrial hyperfusion, thereby affected the mitochondrial function. Taken together, our study suggests that impaired Parkin causes mitochondrial hyperfusion due to two reasons: (1) Parkin defect impairs Pink1-Parkin axis-mediated Marf degradation, which promotes mitochondrial fusion; (2) Parkin defect causes mRpL18 accumulation, which inhibits Drp1/Fis1-mediated mitochondrial fission. These two ways function together to drive Parkin-mediated mitochondrial hyperfusion. Therefore, knockdown of either marf or mRpL18 can prevent mitochondrial hyperfusion, leading to the rescue of Parkin defect-triggered fly wing phenotypes. Overall, our study unveils a new facet of how Parkin regulates mitochondrial morphology to affect mitochondrial function, which provides new insights for the understanding and treatment of Parkinson's disease.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"27 1","pages":"110208"},"PeriodicalIF":4.8,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143932532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of human Shu complex in ATP-dependent regulation of RAD51 filaments during homologous recombination-associated DNA damage response.","authors":"Sam S H Chu,Guangxin Xing,Hong Ling","doi":"10.1016/j.jbc.2025.110212","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110212","url":null,"abstract":"Error-free DNA lesion bypass is an important pathway in DNA damage tolerance. The Shu complex facilitates this process by promoting homologous recombination (HR) to bypass DNA damage. Biochemical analysis of the human Shu complex homolog, hSWS1-SWSAP1, offers valuable insights into the HR-associated DNA damage response. Here, we biochemically characterized the human Shu complex and examined its interactions with RAD51 filaments, which are essential in HR. Using fluorescence polarization assays, we first revealed that hSWS1-SWSAP1 preferentially binds DNA with an exposed 5' end in the presence of adenine nucleotides. We then investigated and validated the DNA-stimulated ATPase activity of hSWS1-SWSAP1 through site-specific mutagenesis, revealing that DNA with an exposed 5' end is the most efficient in enhancing this activity. Furthermore, we showed that hSWS1-SWSAP1 initially interacts with RAD51 filaments at the 5' end and modulates the properties of the nucleoprotein filaments using fluorescence-based assays. Our findings revealed that hSWS1-SWSAP1 induces conformational changes in RAD51 filaments in an ATP-hydrolysis-dependent manner, while its stabilization of the filaments depends on ATP binding. This work provides mechanistic insights into the regulation of RAD51 filaments in HR-associated DNA damage tolerance.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"50 1","pages":"110212"},"PeriodicalIF":4.8,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143932533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NOTCH2 disrupts the synovial fibroblast identity and the inflammatory response of epiphyseal chondrocytes.","authors":"Ernesto Canalis,Rosa Guzzo,Lauren Schilling,Emily Denker","doi":"10.1016/j.jbc.2025.110206","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110206","url":null,"abstract":"Notch signaling plays a fundamental role in the inflammatory response and has been linked to the pathogenesis of osteoarthritis in murine models of the disease and in humans. To address how Notch signaling modifies transcriptomes and cell populations, we examined the effects of NOTCH2 in chondrocytes from mice harboring a NOTCH2 gain-of-function mutation (Notch2tm1.1Ecan) and a conditional NOTCH2 gain-of-function model expressing the NOTCH2 intracellular domain (NICD2) from the Rosa26 locus (R26-NICD2 mice). Bulk RNA-Sequencing (RNA-Seq) of primary epiphyseal cells from both gain-of-function models established increased expression of pathways associated with the phagosome, genes linked to osteoclast activity in rheumatoid arthritis signaling and pulmonary fibrosis signaling. Expression of genes linked to collagen degradation was enhanced in Notch2tm1.1Ecan cells, while genes related to osteoarthritis pathways were increased in NICD2-expressing cells. Single cell (sc)RNA-Seq of cultured Notch2tm1.1Ecan cells revealed clusters of cells related to limb mesenchyme, chondrogenic cells and fibroblasts including articular synovial fibroblasts. Pseudotime trajectory revealed close associations among clusters in control cultures, but the cluster of articular/synovial fibroblasts was disrupted in cells from Notch2tm1.1Ecan mice. ScRNA-Seq showed similarities in the cluster distributions and pseudotime trajectories of NICD2-expressing and control cells, except for altered progression in a cluster of NICD2-expressing cells. In conclusion, NOTCH2 enhances the activity of pathways associated with inflammation in epiphyseal chondrocytes and disrupts the transcriptome profile of articular/synovial fibroblasts.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"105 1","pages":"110206"},"PeriodicalIF":4.8,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143932402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extent of N-glycosylation of the metalloproteinase inhibitor and cytokine TIMP-1 determines pancreatic cancer cell proliferation and survival via CD63.","authors":"Daniel Häußler,Damjan Manevski,Julian Frädrich,Vanessa Brunner,Olga Prokopchuk,Alexander Sommer,Batu Toledo,Percy Knolle,Marc E Martignoni,Helmut Friess,Paul Waterhouse,Achim Krüger","doi":"10.1016/j.jbc.2025.110211","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110211","url":null,"abstract":"Glycosylation emerges as a critical determinant of protein function in cancer, yet its impact on multifunctional secreted factors remains understudied. Here, we identified tissue inhibitor of metalloproteinases-1 (TIMP-1), a glycoprotein with glycosylation sites at N30 and N78 harboring both a canonical anti-proteolytic and non-canonical cytokine-like activity, as one of the most-upregulated secreted glycoproteins circulating in the blood of pancreatic cancer (PC) patients. Whereas plasma from healthy donors contained similar amounts of double- (TIMP-1glyc1/1), single-(N78 and not N30) (TIMP-1glyc0/1), and non-glycosylated (TIMP-1glyc0/0) TIMP-1, TIMP-1glyc1/1 predominated in plasma from PC patients. scRNAseq and in vitro validation linked this shift to tumor progression-associated upregulation of the oligosaccharyltransferase (OST)-complex in epithelial cells. In human PC cell lines, OST complex activity was critical for synthesis of TIMP-1glyc1/1. Importantly, tumor cell-survival and proliferation-promoting activity via CD63 were dependent on TIMP-1 glycosylation, which required N30-glycosylation. In contrast, glycosylation was not necessary for the anti-proteolytic activity of TIMP-1 towards different matrix metalloproteinases (MMPs) (collagenases MMP-1, MMP-8; gelatinases MMP-2, MMP-9; stromelysin MMP-3; Matrilysin MMP-7) but modulated the respective inhibitory efficacy. Analysis of a published glycoproteome data set, allowing assessment of individual glycosylation site occupancy in TIMP-1, revealed that N30 site occupation correlated with poor survival, while N78 site occupation showed no prognostic value, corroborating the impact of double-glycosylation of TIMP-1, as observed in patients, on tumor-promotion. The glycosylation-dependent modulation of the multifunctionality of tumor-secreted TIMP-1 thus provide a molecular basis for its long-debated cancer-promoting role. Finally, it exemplifies the impact of glycosylation macroheterogeneity on disease-relevant modulation of protein function.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"39 1","pages":"110211"},"PeriodicalIF":4.8,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143932530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Smooth muscle Cxcl12 contributions to vascular remodeling in flow and hypoxia-induced pulmonary hypertension.","authors":"Timothy Klouda,Savas T Tsikis,Thomas I Hirsch,Yunhye Kim,Yan Li,Julia Gaal,Zhiyue Zhao,Ingeborg Friehs,John Y-J Shyy,Benjamin A Raby,Mark Puder,Ke Yuan","doi":"10.1016/j.jbc.2025.110207","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110207","url":null,"abstract":"Patients with congenital heart disease (CHD) causing significant left-to-right shunting of blood are at risk of developing pulmonary arterial hypertension (PAH). However, the underlying mechanism by which pulmonary overcirculation and shear stress drive vascular remodeling remains poorly understood. Our study established a \"two-hit\" murine model of severe pulmonary hypertension (PH) by combining left pneumonectomy (LP) and chronic hypoxia (LP/Hx). Using transgenic reporter lines, immunofluorescence (IF) staining, and advanced microscopy, we conducted cell-lineage tracing for vascular cells, including smooth muscle cells (SMCs), endothelial cells (ECs), and pericytes. Our findings reveal that SMCs are key contributors to the distal arteriolar remodeling following LP and LP/Hx. PCR analysis of SMCs isolated from LP/Hx animals demonstrated upregulation of markers associated with contractility, proliferation, and Cxcl12 expression. Consistently, CXCL12 was found to be overexpressed in the SMC layer of pulmonary vessels from patients with PAH-CHD. Lastly, in vitro experiments with healthy human pulmonary artery SMCs showed that laminar shear stress induces CXCL12 upregulation. These findings provide novel insights into the role of SMCs in flow-induced vascular remodeling and their mechanosensitive response to shear stress. This murine model of severe PH is a valuable tool for future research and developing targeted therapeutics for patients with PAH.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"145 1","pages":"110207"},"PeriodicalIF":4.8,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143932399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ProOvErlap: Assessing feature proximity/overlap and testing statistical significance from genomic intervals.","authors":"Nicolò Gualandi,Alessio Bertozzo,Claudio Brancolini","doi":"10.1016/j.jbc.2025.110209","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110209","url":null,"abstract":"Feature overlap is a critical concept in bioinformatics and occurs when two genomic intervals, usually represented as BED files, are located in the same genomic regions. Instead, feature proximity refers to the spatial proximity of genomic elements. For example, promoters typically overlap or are close to the genes they regulate. Overlap and proximity are also important in epigenetic studies. Here, the overlap of regions enriched for specific epigenetic modifications or accessible chromatin can elucidate complex molecular phenotypes. Consequently, the ability to analyze and interpret feature overlap and proximity is essential for understanding the biological processes that contribute to a given phenotype. To address this need, we present a computational method capable of analyzing data represented in the BED format. This method aims to quantitatively assess the degree of proximity or overlap between genomic features and to determine the statistical significance of these events in the context of a non-parametric randomization test. The aim is to understand whether the observed state differs from what would be expected by chance. The method is designed to be easy to use, requiring only a single command line to run, allowing straightforward overlap and proximity analysis. It also provides clear visualizations and publication-quality figures. In conclusion, this study highlights the importance of feature overlap and proximity in epigenetic studies and presents a method to improve the systematic assessment and interpretation of these features. A new resource for identifying biologically significant interactions between genomic features in both healthy and disease states.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"3 1","pages":"110209"},"PeriodicalIF":4.8,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143932535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}