BMC BiologyPub Date : 2025-03-12DOI: 10.1186/s12915-025-02186-y
Jie Su, Yanyan Yang, Daqing Wang, Hong Su, Feifei Zhao, Chuanqiang Zhang, Min Zhang, Xiunan Li, Tingyi He, Xihe Li, Ying Tian, Biao Song, Chao Chen, Yongli Song, Guifang Cao
{"title":"A dynamic transcriptional cell atlas of testes development after birth in Hu sheep.","authors":"Jie Su, Yanyan Yang, Daqing Wang, Hong Su, Feifei Zhao, Chuanqiang Zhang, Min Zhang, Xiunan Li, Tingyi He, Xihe Li, Ying Tian, Biao Song, Chao Chen, Yongli Song, Guifang Cao","doi":"10.1186/s12915-025-02186-y","DOIUrl":"10.1186/s12915-025-02186-y","url":null,"abstract":"<p><strong>Background: </strong>Testes development is a fundamental process in sexual development and reproduction. The testes undergo dramatic structural changes during development, including the proliferation and differentiation of somatic cells such as Sertoli cells, Leydig cells, and myoid cells, as well as the maturation of spermatogonia. However, little is known about the onset of spermatogenesis and cell proliferation and maturation in the spermatogonial niche in large animals.</p><p><strong>Results: </strong>We used single-cell RNA sequencing (scRNA-seq) to profile nearly 100,000 cells from Hu sheep testes across seven developmental stages (birth, prepuberty, puberty, and adulthood). We constructed single-cell transcriptomic atlases and identified distinct spermatogonial subtypes, revealing dynamic gene expression patterns during spermatogenesis. Notably, we observed that two distinct Sertoli cell states converge into a mature population during puberty. Additionally, we identified a common prepubertal progenitor for Leydig and myoid cells, with Leydig cells transitioning through progenitor and immature stages before reaching maturity.</p><p><strong>Conclusions: </strong>Our study provides a comprehensive atlas of Hu sheep testes development, revealing key insights into the dynamic changes and regulatory mechanisms of spermatogenesis and somatic cell maturation from birth to adulthood. These findings offer new perspectives on testicular development in large mammals and support future research on reproductive biology and breeding strategies.</p>","PeriodicalId":9339,"journal":{"name":"BMC Biology","volume":"23 1","pages":"78"},"PeriodicalIF":4.4,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905504/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143613479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BMC BiologyPub Date : 2025-03-11DOI: 10.1186/s12915-025-02169-z
Alicja Witwicka, Federico López-Osorio, Andres Arce, Richard J Gill, Yannick Wurm
{"title":"Acute and chronic pesticide exposure trigger fundamentally different molecular responses in bumble bee brains.","authors":"Alicja Witwicka, Federico López-Osorio, Andres Arce, Richard J Gill, Yannick Wurm","doi":"10.1186/s12915-025-02169-z","DOIUrl":"10.1186/s12915-025-02169-z","url":null,"abstract":"<p><strong>Background: </strong>Beneficial insects, including pollinators, encounter various pesticide exposure conditions, from brief high-concentration acute exposure to continuous low-level chronic exposure. To effectively assess the environmental risks of pesticides, it is critical to understand how different exposure schemes influence their effects. Unfortunately, this knowledge remains limited. To clarify whether different exposure schemes disrupt the physiology of pollinators in a similar manner, we exposed bumble bees to acute or chronic treatments of three different pesticides: acetamiprid, clothianidin, or sulfoxaflor. Genome-wide gene expression profiling enabled us to compare the effects of these treatments on the brain in a high-resolution manner.</p><p><strong>Results: </strong>There were two main findings: First, acute and chronic exposure schemes largely affected non-overlapping sets of genes. Second, different pesticides under the same exposure scheme showed more comparable effects than the same pesticide under different exposure schemes. Each exposure scheme induced a distinct gene expression profile. Acute exposure mainly caused upregulation of genes linked to the stress response mechanisms, like peroxidase and detoxification genes, while chronic exposure predominantly affected immunity and energy metabolism.</p><p><strong>Conclusions: </strong>Our findings show that the mode of exposure is critical in determining the molecular effects of pesticides. These results signal the need for safety testing practices to better consider mode-of-exposure dependent effects and suggest that transcriptomics can support such improvements.</p>","PeriodicalId":9339,"journal":{"name":"BMC Biology","volume":"23 1","pages":"72"},"PeriodicalIF":4.4,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11900027/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BMC BiologyPub Date : 2025-03-11DOI: 10.1186/s12915-025-02180-4
Robert Mukiibi, Serena Ferraresso, Rafaella Franch, Luca Peruzza, Giulia Dalla Rovere, Massimiliano Babbucci, Daniela Bertotto, Anna Toffan, Francesco Pascoli, Sara Faggion, Carolina Peñaloza, Costas S Tsigenopoulos, Ross D Houston, Luca Bargelloni, Diego Robledo
{"title":"Integrated functional genomic analysis identifies regulatory variants underlying a major QTL for disease resistance in European sea bass.","authors":"Robert Mukiibi, Serena Ferraresso, Rafaella Franch, Luca Peruzza, Giulia Dalla Rovere, Massimiliano Babbucci, Daniela Bertotto, Anna Toffan, Francesco Pascoli, Sara Faggion, Carolina Peñaloza, Costas S Tsigenopoulos, Ross D Houston, Luca Bargelloni, Diego Robledo","doi":"10.1186/s12915-025-02180-4","DOIUrl":"10.1186/s12915-025-02180-4","url":null,"abstract":"<p><strong>Background: </strong>Viral nervous necrosis (VNN) is an important viral disease threatening global aquaculture sustainability and affecting over 50 farmed and ecologically important fish species. A major QTL for resistance to VNN has been previously detected in European sea bass, but the underlying causal gene(s) and mutation(s) remain unknown. To identify the mechanisms and genetic factors underpinning resistance to VNN in European sea bass, we employed integrative analyses of multiple functional genomics assays in European sea bass.</p><p><strong>Results: </strong>The estimated heritability of VNN resistance was high (h<sup>2</sup> ~ 0.40), and a major QTL explaining up to 38% of the genetic variance of the trait was confirmed on chromosome 3, with individuals with the resistant QTL genotype showing a 90% survivability against a VNN outbreak. Whole-genome resequencing analyses narrowed the location of this QTL to a small region containing 4 copies of interferon alpha inducible protein 27-like 2A (IFI27L2A) genes, and one copy of the interferon alpha inducible protein 27-like 2 (IFI27L2) gene. RNA sequencing revealed a clear association between the QTL genotype and the expression of two of the IFI27L2A genes, and the IFI27L2 gene. Integration with chromatin accessibility and histone modification data pinpointed two SNPs in active regulatory regions of two of these genes (IFI27L2A and IFI27L2), and transcription factor binding site gains for the resistant alleles were predicted. These alleles, particularly the SNP variant CHR3:10,077,301, exhibited higher frequencies (0.55 to 0.77) in Eastern Mediterranean Sea bass populations, which show considerably higher levels of resistance to VNN, as compared to susceptible West Mediterranean and Atlantic populations (0.15-0.25).</p><p><strong>Conclusions: </strong>The SNP variant CHR3:10,077,301, through modulation of IFI27L2 and IFI27L2A genes, is likely the causative mutation underlying resistance to VNN in European sea bass. This is one of the first causative mutations discovered for disease resistance traits in fish and paves the way for marker-assisted selection as well as biotechnological approaches to enhance resistance to VNN in European sea bass and other susceptible species.</p>","PeriodicalId":9339,"journal":{"name":"BMC Biology","volume":"23 1","pages":"75"},"PeriodicalIF":4.4,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11899128/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BMC BiologyPub Date : 2025-03-11DOI: 10.1186/s12915-025-02177-z
Zhecheng Zhou, Jinhang Wei, Mingzhe Liu, Linlin Zhuo, Xiangzheng Fu, Quan Zou
{"title":"AnomalGRN: deciphering single-cell gene regulation network with graph anomaly detection.","authors":"Zhecheng Zhou, Jinhang Wei, Mingzhe Liu, Linlin Zhuo, Xiangzheng Fu, Quan Zou","doi":"10.1186/s12915-025-02177-z","DOIUrl":"10.1186/s12915-025-02177-z","url":null,"abstract":"<p><strong>Background: </strong>Single-cell RNA sequencing (scRNA-seq) is now essential for cellular-level gene expression studies and deciphering complex gene regulatory mechanisms. Deep learning methods, when combined with scRNA-seq technology, transform gene regulation research into graph link prediction tasks. However, these methods struggle to mitigate the impact of noisy data in gene regulatory networks (GRNs) and address the significant imbalance between positive and negative links.</p><p><strong>Results: </strong>Consequently, we introduce the AnomalGRN model, focusing on heterogeneity and sparsification to elucidate complex regulatory mechanisms within GRNs. Initially, we consider gene pairs as nodes to construct new networks, thereby converting gene regulation prediction into a node prediction task. Considering the imbalance between positive and negative links in GRNs, we further adapt this issue into a graph anomaly detection (GAD) task, marking the first application of anomaly detection to GRN analysis. Introducing the cosine metric rule enables the AnomalGRN model to differentiate between homogeneity and heterogeneity among nodes in the reconstructed GRNs. The adoption of graph structure sparsification technology reduces noisy data impact and optimizes node representation.</p><p><strong>Conclusions: </strong></p>","PeriodicalId":9339,"journal":{"name":"BMC Biology","volume":"23 1","pages":"73"},"PeriodicalIF":4.4,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11900578/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BMC BiologyPub Date : 2025-03-11DOI: 10.1186/s12915-025-02182-2
Xiaoyong Pan, Yi Fang, Xiaojian Liu, Xiaoyu Guo, Hong-Bin Shen
{"title":"RBPsuite 2.0: an updated RNA-protein binding site prediction suite with high coverage on species and proteins based on deep learning.","authors":"Xiaoyong Pan, Yi Fang, Xiaojian Liu, Xiaoyu Guo, Hong-Bin Shen","doi":"10.1186/s12915-025-02182-2","DOIUrl":"10.1186/s12915-025-02182-2","url":null,"abstract":"<p><strong>Background: </strong>RNA-binding proteins (RBPs) play crucial roles in many biological processes, and computationally identifying RNA-RBP interactions provides insights into the biological mechanism of diseases associated with RBPs.</p><p><strong>Results: </strong>To make the RBP-specific deep learning-based RBP binding sites prediction methods easily accessible, we developed an updated easy-to-use webserver, RBPsuite 2.0, with an updated web interface for predicting RBP binding sites from linear and circular RNA sequences. RBPsuite 2.0 has a higher coverage on the number of supported RBPs and species compared to the original RBPsuite, supporting an increased number of RBPs from 154 to 353 and expanding the supported species from one to seven. Additionally, RBPsuite 2.0 replaces the CRIP built into RBPsuite 1.0 with iDeepC, a more accurate RBP binding site predictor for circular RNAs. Furthermore, RBPsuite 2.0 estimates the contribution score of individual nucleotides on the input sequences as potential binding motifs and links to the UCSC browser track for better visualization of the prediction results.</p><p><strong>Conclusions: </strong>RBPsuite 2.0 is an updated, more comprehensive webserver for predicting RBP binding sites in both linear and circular RNA sequences. It supports more RBPs and species and provides more accurate predictions for circular RNAs. The tool is freely available at http://www.csbio.sjtu.edu.cn/bioinf/RBPsuite/ .</p>","PeriodicalId":9339,"journal":{"name":"BMC Biology","volume":"23 1","pages":"74"},"PeriodicalIF":4.4,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11899677/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BMC BiologyPub Date : 2025-03-06DOI: 10.1186/s12915-025-02162-6
Nicole Vüllings, Alina Airich, Ekaterina Seib, Tobias Troost, Thomas Klein
{"title":"Another tail of two sites: activation of the Notch ligand Delta by Mindbomb1.","authors":"Nicole Vüllings, Alina Airich, Ekaterina Seib, Tobias Troost, Thomas Klein","doi":"10.1186/s12915-025-02162-6","DOIUrl":"10.1186/s12915-025-02162-6","url":null,"abstract":"<p><strong>Background: </strong>Notch signalling plays a crucial role in many developmental, homoeostatic and pathological processes in metazoans. The pathway is activated by binding of the ligand to the Notch receptor, which changes the conformation of the receptor by exerting a pulling force. The pulling force is generated by the endocytosis of the interacting ligand into the signal-sending cell. Endocytosis of ligands requires the action of the E3 ligases Mindbomb1 (Mib1) and Neuralized (Neur) that ubiquitylate lysines (Ks) of their intracellular domains. It has been shown that human MIB1 binds JAGGED1 (JAG1) via a bipartite binding motif in its ICD. This interaction is required for the activation of JAG1. However, it is not known whether this bipartite binding mode is of general importance. It is also not rigorously tested whether it occurs in vivo. Moreover, it is not known whether Mib1 ubiquitylates specific Ks in the ICD of ligands, or is rather non-selective.</p><p><strong>Results: </strong>We therefore investigated how Mib1 interacts with the Notch ligand Delta of Drosophila in an in vivo trans-activation assay and determined the Ks which are required for signalling. We show that the activation of Dl by Mib1 follows similar rules as has been found for mammalian MIB1 and JAG1. We present evidence that a combination of six Ks of the ICD is required for the full signalling activity of Dl by Mib1, with K742 being the most important one.</p><p><strong>Conclusions: </strong>Altogether, our analysis further reveals the rules of Mib1-mediated DSL-ligand-dependent Notch-signalling.</p>","PeriodicalId":9339,"journal":{"name":"BMC Biology","volume":"23 1","pages":"71"},"PeriodicalIF":4.4,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11887331/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143572137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BMC BiologyPub Date : 2025-03-05DOI: 10.1186/s12915-025-02175-1
Jie Sheng, Xuemei Zhang, Weihong Liang, Junfang Lyu, Bei Zhang, Jie Min, Austin Xu, Xingyu Xu, Jennifer W Li, Jian-Liang Li, Rui Zhou, Wei Liu
{"title":"The circular RNA circbabo(5,6,7,8S) regulates lipid metabolism and neuronal integrity via TGF-β/ROS/JNK/SREBP signaling axis in Drosophila.","authors":"Jie Sheng, Xuemei Zhang, Weihong Liang, Junfang Lyu, Bei Zhang, Jie Min, Austin Xu, Xingyu Xu, Jennifer W Li, Jian-Liang Li, Rui Zhou, Wei Liu","doi":"10.1186/s12915-025-02175-1","DOIUrl":"10.1186/s12915-025-02175-1","url":null,"abstract":"<p><strong>Background: </strong>Lipid droplets (LDs) are dynamic cytoplasmic lipid-storing organelles that play a pivotal role in maintaining cellular energy balance, lipid homeostasis, and metabolic signaling. Dysregulation of lipid metabolism, particularly excessive lipogenesis, contributes to the abnormal accumulation of LDs in the nervous system, which is associated with several neurodegenerative diseases. Circular RNAs (circRNAs) are a new class of non-coding and regulatory RNAs that are widely expressed in eukaryotes. However, only a subset has been functionally characterized. Here, we identified and functionally characterized a new circular RNA circbabo(5,6,7,8S) that regulates lipogenesis and neuronal integrity in Drosophila melanogaster.</p><p><strong>Results: </strong>circbabo(5,6,7,8S) is derived from the babo locus which encodes the type I receptor for transforming growth factor β (TGF-β). Depletion of circbabo(5,6,7,8S) in flies causes elevated lipid droplet accumulation, progressive photoreceptor cell loss and shortened lifespan, phenotypes that are rescued by restoring circbabo(5,6,7,8S) expression. In addition, RNA-seq and epistasis analyses reveal that these abnormalities are caused by aberrant activation of the SREBP signaling pathway. Furthermore, circbabo(5,6,7,8S)-depleted tissues display enhanced activation of the TGF-β signaling pathway and compromised mitochondrial function, resulting in upregulation of reactive oxygen species (ROS). Moreover, we provide evidence that circbabo(5,6,7,8S) encodes the protein circbabo(5,6,7,8S)-p, which inhibits TGF-β signaling by interfering with the assembly of babo/put receptor heterodimer complex. Lastly, we show that dysregulation of the ROS/JNK/SREBP signaling cascade is responsible for the LD accumulation, neurodegeneration, and shortened lifespan phenotypes elicited by circbabo(5,6,7,8S) depletion.</p><p><strong>Conclusions: </strong>Our study demonstrates the physiological role of the protein-coding circRNA circbabo(5,6,7,8S) in regulating lipid metabolism and neuronal integrity.</p>","PeriodicalId":9339,"journal":{"name":"BMC Biology","volume":"23 1","pages":"69"},"PeriodicalIF":4.4,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881384/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143555948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BMC BiologyPub Date : 2025-03-05DOI: 10.1186/s12915-025-02176-0
Man Luo, Junjie Zhao, Juha Merilä, Rowan D H Barrett, Baocheng Guo, Juntao Hu
{"title":"The interplay between epigenomic and transcriptomic variation during ecotype divergence in stickleback.","authors":"Man Luo, Junjie Zhao, Juha Merilä, Rowan D H Barrett, Baocheng Guo, Juntao Hu","doi":"10.1186/s12915-025-02176-0","DOIUrl":"10.1186/s12915-025-02176-0","url":null,"abstract":"<p><strong>Background: </strong>Populations colonizing contrasting environments are likely to undergo adaptive divergence and evolve ecotypes with locally adapted phenotypes. While diverse molecular mechanisms underlying ecotype divergence have been identified, less is known about their interplay and degree of divergence.</p><p><strong>Results: </strong>Here we integrated epigenomic and transcriptomic data to explore the interactions among gene expression, alternative splicing, DNA methylation, and microRNA expression to gauge the extent to which patterns of divergence at the four molecular levels are aligned in a case of postglacial divergence between marine and freshwater ecotypes of nine-spined sticklebacks (Pungitius pungitius). Despite significant genome-wide associations between epigenomic and transcriptomic variation, we found largely non-parallel patterns of ecotype divergence across epigenomic and transcriptomic levels, with predominantly nonoverlapping (ranging from 43.40 to 87.98%) sets of differentially expressed, spliced and methylated genes, and candidate genes targeted by differentially expressed miRNA between the ecotypes. Furthermore, we found significant variation in the extent of ecotype divergence across different molecular mechanisms, with differential methylation and differential splicing showing the highest and lowest extent of divergence between ecotypes, respectively. Finally, we found a significant enrichment of genes associated with ecotype divergence in differential methylation.</p><p><strong>Conclusions: </strong>Our results suggest a nuanced relationship between epigenomic and transcriptomic processes, with alignment at the genome-wide level masking relatively independent effects of different molecular mechanisms on ecotype divergence at the gene level.</p>","PeriodicalId":9339,"journal":{"name":"BMC Biology","volume":"23 1","pages":"70"},"PeriodicalIF":4.4,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881503/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143555950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Switching of OAS1 splicing isoforms overcomes SNP-derived vulnerability to SARS-CoV-2 infection.","authors":"Kei Iida, Masahiko Ajiro, Akiko Nakano-Kobayashi, Yukiko Muramoto, Toru Takenaga, Masatsugu Denawa, Ryo Kurosawa, Takeshi Noda, Masatoshi Hagiwara","doi":"10.1186/s12915-025-02173-3","DOIUrl":"10.1186/s12915-025-02173-3","url":null,"abstract":"<p><strong>Background: </strong>The SARS-CoV-2 pandemic provided important insights into the relationship between infectious diseases and the human genome. A genomic region encoding the 2'-5'-oligoadenylate synthetase (OAS) family proteins that sense viral genomic RNAs and trigger an antiviral response contains single nucleotide polymorphisms (SNPs) associated with SARS-CoV-2 infection susceptibility. A high-risk SNP identified at the splice acceptor site of OAS1 exon 6-a terminal exon-alters the proportion of various splicing isoforms of OAS1 and its activity. However, the actual causality of this SNP or splicing to infection susceptibility remains unknown.</p><p><strong>Results: </strong>In this study, it was found that serine-arginine-rich splicing factor 6 (SRSF6) binds to the splice donor site of the human OAS1 exon 5. SRSF6 determines the selected alternative terminal exon when the risk allele disrupts the splice acceptor site. Subsequently, an inhibitor for CDC-like kinase was rationally selected as a candidate splicing modulator. RNA-Seq and RT-PCR analyses revealed that this inhibitor can induce splice switching of OAS1 mRNAs in the human lung adenocarcinoma cell line Calu-3. Under the inhibitor treatment, the cells exhibited reduced SARS-CoV-2 infection rates. Meanwhile, the colonic epithelial cell line Caco-2 expressed non-risk type OAS1 mRNA isoforms that did not undergo splice-switching or demonstrate altered SARS-CoV-2 sensitivity following treatment with the inhibitor.</p><p><strong>Conclusions: </strong>These results indicate that a high-risk SNP in OAS1 influences cell susceptibility to SARS-CoV-2 infection by inducing splice-switching at its terminal exon. Additionally, chemical splicing modifiers may prove beneficial in overcoming this genomic vulnerability.</p>","PeriodicalId":9339,"journal":{"name":"BMC Biology","volume":"23 1","pages":"60"},"PeriodicalIF":4.4,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11874701/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BMC BiologyPub Date : 2025-03-03DOI: 10.1186/s12915-025-02137-7
He Fang, Ana R Tronco, Giancarlo Bonora, Truong Nguyen, Jitendra Thakur, Joel B Berletch, Galina N Filippova, Steven Henikoff, Jay Shendure, William S Noble, Zhijun Duan, Christine M Disteche, Xinxian Deng
{"title":"CTCF-mediated insulation and chromatin environment modulate Car5b escape from X inactivation.","authors":"He Fang, Ana R Tronco, Giancarlo Bonora, Truong Nguyen, Jitendra Thakur, Joel B Berletch, Galina N Filippova, Steven Henikoff, Jay Shendure, William S Noble, Zhijun Duan, Christine M Disteche, Xinxian Deng","doi":"10.1186/s12915-025-02137-7","DOIUrl":"10.1186/s12915-025-02137-7","url":null,"abstract":"<p><strong>Background: </strong>Genes that escape X-chromosome inactivation (XCI) in female somatic cells vary in number and levels of escape among mammalian species and tissues, potentially contributing to species- and tissue-specific sex differences. CTCF, a master chromatin conformation regulator, is enriched at escape regions and may play an important role in regulating escape, but the molecular mechanisms remain elusive.</p><p><strong>Results: </strong>CTCF binding profiles and epigenetic features were systematically examined at escape genes (escapees) using mouse allelic systems with skewed XCI to distinguish the inactive X (Xi) and active X (Xa) chromosomes. We found that six constitutive and two facultative escapees are located inside 30-800 kb domains marked by convergent arrays of CTCF binding sites, consistent with the formation of chromatin loops. Facultative escapees show clear differences in CTCF binding depending on their XCI status in specific cell types/tissues. In addition, sets of strong and in some cases divergent CTCF binding sites located at the boundary between an escapee and its adjacent neighbors subject to XCI would also help insulate domains. Indeed, deletion but not inversion of a CTCF binding site at the boundary between the facultative escapee Car5b and its silent neighbor Siah1b results in a dramatic reduction of Car5b escape. This is associated with reduced CTCF and cohesin binding, which indicates loss of looping and insulation and is supported by 3C combined with Hi-C analysis. In addition, enrichment in the repressive mark H3K27me3 invades the Car5b domain in deleted cells, consistent with loss of expression from the Xi. In contrast, cells with an inversion of the CTCF binding site retain CTCF and cohesin binding, as well as looping, in line with persistence of escape. Interestingly, the levels of escape increase in cells with deletion of either Dxz4, which disrupts the Xi-specific compact 3D structure, or Firre, which results in lower H3K27me3 enrichment on the Xi, indicating that the structural and epigenetic features of the Xi constrain escape from XCI in wild type conditions.</p><p><strong>Conclusions: </strong>Taken together, our findings support the idea that escape from XCI in female somatic cells is modulated by both the topological insulation of domains via CTCF binding and the surrounding heterochromatin environment.</p>","PeriodicalId":9339,"journal":{"name":"BMC Biology","volume":"23 1","pages":"68"},"PeriodicalIF":4.4,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11874400/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}