Nucleic Acids Research最新文献_第3页

Nuclear actin-dependent Meg3 expression suppresses metabolic genes by affecting the chromatin architecture at sites of elevated H3K27 acetylation levels

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2025-04-14 DOI: 10.1093/nar/gkaf280

Nadine Hosny El Said, Wael Abdrabou, Syed Raza Mahmood, Tomas Venit, Youssef Idaghdour, Piergiorgio Percipalle

{"title":"Nuclear actin-dependent Meg3 expression suppresses metabolic genes by affecting the chromatin architecture at sites of elevated H3K27 acetylation levels","authors":"Nadine Hosny El Said, Wael Abdrabou, Syed Raza Mahmood, Tomas Venit, Youssef Idaghdour, Piergiorgio Percipalle","doi":"10.1093/nar/gkaf280","DOIUrl":"https://doi.org/10.1093/nar/gkaf280","url":null,"abstract":"Nuclear actin mediates enhancer-dependent transcriptional regulation at compartment level, playing critical roles in 3D genome organization. In β-actin depleted cells, H3K27 acetylation is enhanced, directly affecting enhancer-dependent transcriptional regulation and gene expression changes during compartment-switching. Here, we report these mechanisms are influenced by the long non-coding RNA (lncRNA) Meg3. Bulk RNA-seq analysis and qPCR on wild-type (WT), heterozygous (HET), and β-actin knockout (KO) mouse embryonic fibroblasts (MEFs) show that β-actin depletion significantly alters expression of several lncRNAs, including Meg3. Results from ChIRP-seq, ChIRP-MS, and fRIP-qPCR revealed that in β-actin KO cells, Meg3 becomes enriched and binds to H3K27 acetylation marks within gene regulatory regions. By integrating RNA-seq, H3K27 acetylation ChIP-seq, ATAC-seq, and HiC-seq data through activity by contact (ABC) analysis, we discovered Meg3 binding disrupts promoter–enhancer interactions in β-actin KO cells. These results, combined with metabolomics in WT, HET, and β-actin KO MEFs, show Meg3 binding to regulatory regions at sites of increased H3K27 acetylation impairs the expression of genes involved in the synthesis of chondroitin, heparan, dermatan sulfate, and phospholipases. We propose that in β-actin KO cells Meg3 binds to H3K27 acetylation levels. This interferes with promoter–enhancer interactions, disrupts genome organization, and downregulates gene expression and key metabolic pathways.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"239 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143827651","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}

引用次数: 0

LIET model: capturing the kinetics of RNA polymerase from loading to termination

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2025-04-14 DOI: 10.1093/nar/gkaf246

Jacob T Stanley, Georgia E F Barone, Hope A Townsend, Rutendo F Sigauke, Mary A Allen, Robin D Dowell

{"title":"LIET model: capturing the kinetics of RNA polymerase from loading to termination","authors":"Jacob T Stanley, Georgia E F Barone, Hope A Townsend, Rutendo F Sigauke, Mary A Allen, Robin D Dowell","doi":"10.1093/nar/gkaf246","DOIUrl":"https://doi.org/10.1093/nar/gkaf246","url":null,"abstract":"Transcription by RNA polymerases is an exquisitely regulated step of the central dogma. Transcription is the primary determinant of cell-state, and most cellular perturbations impact transcription by altering polymerase activity. Thus, detecting changes in polymerase activity yields insight into most cellular processes. Nascent run-on sequencing provides a direct readout of polymerase activity, but no tools exist to model all aspects of this activity at genes. We focus on RNA polymerase II—responsible for transcribing protein-coding genes. We present the first model to capture the complete process of gene transcription. For individual genes, this model parameterizes each distinct stage of transcription—loading, initiation, elongation, and termination, hence LIET—in a biologically interpretable Bayesian mixture, which is applied to nascent run-on data. Our improved modeling of loading/initiation demonstrates these stages are characteristically different between sense and antisense strands. Applying LIET to 24 human cell-types, our analysis indicates the position of dissociation (the last step of termination) appears to be highly consistent, indicative of a tightly regulated process. Furthermore, by applying LIET to perturbation experiments, we demonstrate its ability to detect specific changes in pausing (5′ end), strand-bias, and dissociation location (3′ end)—opening the door to differential assessment of transcription at individual stages of individual genes.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"23 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143827674","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}

引用次数: 0

Oxidative stress at telomeres triggers internal DNA loops, TRF1 dissociation, and TRF2-dependent R-loops

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2025-04-12 DOI: 10.1093/nar/gkaf285

Trang Thu Nguyen, Giulia Mazzucco, Eftychia Kyriacou, Thomas Lunardi, Leona Brandl, Wareed Ahmed, Ylli Doksani, Joachim Lingner

{"title":"Oxidative stress at telomeres triggers internal DNA loops, TRF1 dissociation, and TRF2-dependent R-loops","authors":"Trang Thu Nguyen, Giulia Mazzucco, Eftychia Kyriacou, Thomas Lunardi, Leona Brandl, Wareed Ahmed, Ylli Doksani, Joachim Lingner","doi":"10.1093/nar/gkaf285","DOIUrl":"https://doi.org/10.1093/nar/gkaf285","url":null,"abstract":"Telomeres are the nucleoprotein structures at chromosome ends. Telomeres are particularly sensitive to oxidative stress, which can induce telomere damage, shortening, and premature cellular senescence. How oxidative damage influences telomere structure has not been defined. Here, we induce oxidative damage at telomeres using menadione, which damages mitochondria mimicking intrinsic oxidative stress. We find that oxidative stress induces at telomeres single-stranded DNA breaks, internal DNA loop structures, dissociation of the shelterin component TRF1, upregulation of TERRA long noncoding RNA, and increased DNA:RNA hybrid structures known as R-loops. R-loop formation is enhanced not only in cis at telomeres, which show increased TERRA transcription, but also in trans at telomeres at which TERRA transcription is not induced indicating post-transcriptional R-loop formation. Finally, we show that oxidative damage induced R-loop formation requires TRF2, whose R-loop promoting activity may be unleashed upon TRF1 dissociation from telomeres. Altogether, our findings uncover in response to oxidative stress major remodelling of telomeric DNA, RNA, and shelterin complexes, and they unravel a physiological role of TRF2’s ability to stimulate TERRA R-loop formation. We propose that the identified structural changes may facilitate DNA damage signalling and repair pathways to maintain telomere integrity during development and aging.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"37 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143824769","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}

引用次数: 0

Tailoring and reversing m6A editing with sequential RNA bioorthogonal chemistry

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2025-04-12 DOI: 10.1093/nar/gkaf283

Xingyu Liu, Qianqian Qi, Wei Xiong, Yuanyuan Zhang, Wei Shen, Xinyan Xu, Yunting Zhao, Ming Li, Enyi Zhou, Tian Tian, Xiang Zhou

引用次数: 0

Poly-(ADP-ribose) serves as a scaffold for the methyltransferase METTL3/14 complex in the DNA damage response 聚（ADP-核糖）是 DNA 损伤反应中甲基转移酶 METTL3/14 复合物的支架

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2025-04-12 DOI: 10.1093/nar/gkaf244

Claudia Gonzalez-Leal, Jin Cai, Bram A F J de Groot, Andreas Wegerer, Julia Preisser, Martijn S Luijsterburg, Andreas G Ladurner

引用次数: 0

DuplexDiscoverer: a computational method for the analysis of experimental duplex RNA–RNA interaction data DuplexDiscoverer：分析双链 RNA-RNA 相互作用实验数据的计算方法

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2025-04-12 DOI: 10.1093/nar/gkaf266

Egor Semenchenko, Volodymyr Tsybulskyi, Irmtraud M Meyer

{"title":"DuplexDiscoverer: a computational method for the analysis of experimental duplex RNA–RNA interaction data","authors":"Egor Semenchenko, Volodymyr Tsybulskyi, Irmtraud M Meyer","doi":"10.1093/nar/gkaf266","DOIUrl":"https://doi.org/10.1093/nar/gkaf266","url":null,"abstract":"For a few years, it has been possible to experimentally probe the universe of cis and trans RNA–RNA interactions in a transcriptome-wide manner. These experiments give rise to so-called duplex data, i.e. short reads generated via high-throughput sequencing that each encode information on a cis or trans RNA–RNA interaction. These raw duplex data require complex, subsequent computational analyses in order to be interpreted as solid evidence for actual cis and trans RNA–RNA interactions. While several methods have already been proposed to tackle this challenge, almost all of them lack one or more desirable feature—computational efficiency, ability to readily alter the main processing steps and parameter values, p-value estimation for predictions, and interoperability with the common bioinformatics tools for transcriptomics. To overcome these challenges, we present DuplexDiscoverer—a computational method and R package that allows for the efficient, adjustable, and conceptually coherent analysis of duplex data. DuplexDiscoverer is readily adaptable to analysing data from different experimental protocols and its results seamlessly integrate with the most commonly used bioinformatics tools for transcriptomics in R. Most importantly, DuplexDiscoverer generates predictions that are of superior or comparable quality to those of the existing methods while significantly improving time and memory efficiency.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"119 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143824928","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}

引用次数: 0

Analysis of RNA translation with a deep learning architecture provides new insight into translation control

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2025-04-12 DOI: 10.1093/nar/gkaf277

Xiaojuan Fan, Tiangen Chang, Chuyun Chen, Markus Hafner, Zefeng Wang

{"title":"Analysis of RNA translation with a deep learning architecture provides new insight into translation control","authors":"Xiaojuan Fan, Tiangen Chang, Chuyun Chen, Markus Hafner, Zefeng Wang","doi":"10.1093/nar/gkaf277","DOIUrl":"https://doi.org/10.1093/nar/gkaf277","url":null,"abstract":"Accurate annotation of coding regions in RNAs is essential for understanding gene translation. We developed a deep neural network to directly predict and analyze translation initiation and termination sites from RNA sequences. Trained with human transcripts, our model learned hidden rules of translation control and achieved a near perfect prediction of canonical translation sites across entire human transcriptome. Surprisingly, this model revealed a new role of codon usage in regulating translation termination, which was experimentally validated. We also identified thousands of new open reading frames in mRNAs or lncRNAs, some of which were confirmed experimentally. The model trained with human mRNAs achieved high prediction accuracy of canonical translation sites in all eukaryotes and good prediction in polycistronic transcripts from prokaryotes or RNA viruses, suggesting a high degree of conservation in translation control. Collectively, we present TranslationAI (https://www.biosino.org/TranslationAI/), a general and efficient deep learning model for RNA translation that generates new insights into the complexity of translation regulation.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"38 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143824909","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}

引用次数: 0

Chromatin-associated α-satellite RNA maintains chromosome stability by reestablishing SAF-A in the mitotic cell cycle

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2025-04-12 DOI: 10.1093/nar/gkaf294

Bingbing Ren, Yinchun Zhong, Yan Yang, Shuhui Chang, Yalun Li, Mengzhen You, Ge Shan, Xueren Wang, Enguo Chen

{"title":"Chromatin-associated α-satellite RNA maintains chromosome stability by reestablishing SAF-A in the mitotic cell cycle","authors":"Bingbing Ren, Yinchun Zhong, Yan Yang, Shuhui Chang, Yalun Li, Mengzhen You, Ge Shan, Xueren Wang, Enguo Chen","doi":"10.1093/nar/gkaf294","DOIUrl":"https://doi.org/10.1093/nar/gkaf294","url":null,"abstract":"α-Satellite is the largest class of tandem repeats and is located on all human chromosome centromeres. Non-coding α-satellite RNAs have been observed in various cell types and are known to play crucial roles in maintaining genome stability. In this study, we demonstrated that α-satellite RNAs are dynamically expressed, heterogeneous transcripts that are regulated by Aurora kinases and closely associated with centromere chromatin throughout the mitotic cell cycle. We identified scaffold attachment factor A (SAF-A) as a previously uncharacterized α-satellite RNA binding protein. Depletion of either α-satellite RNA or SAF-A resulted in chromosome missegregation, revealing that their concerted action is essential for preserving genome integrity during the mitotic cell cycle. Our result demonstrated that SAF-A is excluded from the chromatin genome-wide during mitosis, and α-satellite RNAs are required for the recruitment of SAF-A upon mitotic exit. Both α-satellite RNAs and SAF-A are essential in safeguarding the human genome against chromosomal instability during mitosis. Moreover, α-satellite RNAs and SAF-A aid in the reassembly of the nuclear lamina. Our results provide novel insights into the features, regulations, and functional roles of α-satellite RNAs and propose a model for the dismantling and reformation of the SAF-A nuclear scaffold during mitosis.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"75 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143824927","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}

引用次数: 0

The PIN1–p38–CtIP signalling axis protects stalled replication forks from deleterious degradation

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2025-04-10 DOI: 10.1093/nar/gkaf278

Francesca Vivalda, Marco Gatti, Letizia Manfredi, Hülya Dogan, Antonio Porro, Giulio Collotta, Ilaria Ceppi, Christine von Aesch, Vanessa van Ackeren, Sebastian Wild, Martin Steger, Begoña Canovas, Monica Cubillos-Rojas, Antoni Riera, Petr Cejka, Angel R Nebreda, Diego Dibitetto, Sven Rottenberg, Alessandro A Sartori

{"title":"The PIN1–p38–CtIP signalling axis protects stalled replication forks from deleterious degradation","authors":"Francesca Vivalda, Marco Gatti, Letizia Manfredi, Hülya Dogan, Antonio Porro, Giulio Collotta, Ilaria Ceppi, Christine von Aesch, Vanessa van Ackeren, Sebastian Wild, Martin Steger, Begoña Canovas, Monica Cubillos-Rojas, Antoni Riera, Petr Cejka, Angel R Nebreda, Diego Dibitetto, Sven Rottenberg, Alessandro A Sartori","doi":"10.1093/nar/gkaf278","DOIUrl":"https://doi.org/10.1093/nar/gkaf278","url":null,"abstract":"Human CtIP plays a critical role in homologous recombination (HR) by promoting the resection of DNA double-strand breaks. Moreover, CtIP maintains genome stability through protecting stalled replication forks from nucleolytic degradation. However, the upstream signalling mechanisms governing the molecular switch between these two CtIP-dependent processes remain largely elusive. Here, we show that phosphorylation of CtIP by the p38α stress kinase and subsequent PIN1-mediated CtIP cis-to-trans isomerization is required for fork stabilization but dispensable for HR. We found that stalled forks are degraded in cells expressing non-phosphorylatable CtIP or lacking PIN1–p38α activity, while expression of a CtIP trans-locked mutant overcomes the requirement for PIN1–p38α in fork protection. We further reveal that Brca1-deficient mammary tumour cells that have acquired PARP inhibitor (PARPi) resistance regain chemosensitivity after PIN1 or p38α inhibition. Collectively, our findings identify the PIN1–p38–CtIP signalling pathway as a critical regulator of replication fork integrity.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"33 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143813768","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}

引用次数: 0

Light-controlled Spo11-less meiotic DNA breaks by MagTAQing lead to chromosomal aberrations. 通过 MagTAQing 光控无 Spo11 减数分裂 DNA 断裂会导致染色体畸变。

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2025-04-10 DOI: 10.1093/nar/gkaf206

Hideyuki Yone,Yuri Kawashima,Hayato Hirai,Arisa H Oda,Moritoshi Sato,Hiromitsu Kono,Kunihiro Ohta

{"title":"Light-controlled Spo11-less meiotic DNA breaks by MagTAQing lead to chromosomal aberrations.","authors":"Hideyuki Yone,Yuri Kawashima,Hayato Hirai,Arisa H Oda,Moritoshi Sato,Hiromitsu Kono,Kunihiro Ohta","doi":"10.1093/nar/gkaf206","DOIUrl":"https://doi.org/10.1093/nar/gkaf206","url":null,"abstract":"TAQing technologies are based on the restriction enzyme-induced DNA double-strand break (DSB) formation in living cells, which results in large-scale genomic rearrangements and phenotypic alterations. Originally, the TAQing system requires heat treatments to activate restriction enzymes, which sometimes leads to cell toxicity or stress responses. Here, we developed a blue-light-controlled MagTAQing system, which induces DSBs exclusively upon blue-light exposure by assembling the split restriction enzymes via Magnet modules. Application of MagTAQing to mitotic budding yeast cells successfully triggered various genomic rearrangements upon blue-light exposure. Since this technology enables the conditional induction of genomic rearrangements in specific cells or tissues, we employed MagTAQing on meiotic yeast cells lacking the recombinase Spo11 to induce artificial DSBs. Consequently, Spo11-independent meiotic DSBs resulted in aneuploidies and nonallelic homologous recombinations between repetitive sequences such as ribosomal DNA and retrotransposons. These results suggest a pivotal role of Spo11-induced recombination in preventing chromosomal abnormality.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"25 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143819157","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}

引用次数: 0