PLoS Genetics最新文献

{"title":"Detecting latent interaction effects when analyzing binary traits.","authors":"Ziang Zhang, Jerald F Lawless, Andrew D Paterson, Lei Sun","doi":"10.1371/journal.pgen.1011822","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011822","url":null,"abstract":"<p><p>In genome-wide association studies (GWAS), it is often desirable to test for interactions, such as gene-environment (G x E) or gene-gene (G x G) interactions, between single-nucleotide polymorphisms (SNPs, G's) and environmental variables (E's). However, directly accounting for interaction is often infeasible, because the interacting variable is latent or the computational burden is too large. For quantitative traits (Y) that are approximately normally distributed, it has been shown that indirect testing on GxE can be done by testing for heteroskedasticity of Y between genotypes. However, when traits are binary, the existing methodology based on testing the heteroskedasticity of the trait across genotypes cannot be generalized. In this paper, we propose an approach to indirectly test interaction effects for binary traits and subsequently propose a joint test that accounts for the main and interaction effects of each SNP during GWAS. The final method is straightforward to implement in practice-it simply involves adding a non-additive (i.e., dominance) term to standard GWAS additive models for binary traits and testing its significance. We illustrate the statistical features including type-I-error control and power of the proposed method through extensive numerical studies. Applying our method to the UK Biobank dataset, we showcase the practical utility of the proposed method, revealing SNPs and genes with strong potential for latent interaction effects.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 8","pages":"e1011822"},"PeriodicalIF":3.7,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12396767/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144975730","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":"Analysis of (p)ppGpp metabolism and signaling using a dynamic luminescent reporter.","authors":"Molly Hydorn, Sathya Narayanan Nagarajan, Elizabeth Fones, Caroline S Harwood, Jonathan Dworkin","doi":"10.1371/journal.pgen.1011691","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011691","url":null,"abstract":"<p><p>As rapidly growing bacteria begin to exhaust nutrients, their growth rate slows, ultimately leading to the non-replicative state of quiescence. Adaptation to nutrient limitation requires widespread metabolic remodeling that is in part mediated by the phosphorylated nucleotides guanosine tetra- and penta-phosphate, collectively (p)ppGpp. We have developed a novel reporter of (p)ppGpp abundance in the Gram-positive bacterium Bacillus subtilis based on the recent identification of a riboswitch that binds (p)ppGpp and modulates transcription via regulation of a transcriptional terminator. Placement of an unstable reporter, firefly luciferase, downstream of the riboswitch allows for sensitive and dynamic assessment of (p)ppGpp. We first confirm that the reporter accurately reflects (p)ppGpp abundance in a variety of well-established conditions. We then proceed to use it to demonstrate the physiological importance of several mechanisms of regulation of (p)ppGpp metabolism previously observed only in vitro including allosteric interactions between (p)ppGpp synthesis enzymes and the hydrolytic activity of a (p)ppGpp synthetase. (p)ppGpp signaling has been implicated in the regulation of gene expression, and we demonstrate a close temporal association between gene expression and (p)ppGpp abundance, indicating a rapid, and therefore likely direct mechanism of (p)ppGpp dependent gene activation. Thus, this reporter provides a new, comprehensive analysis of (p)ppGpp signaling in vivo and offers the potential ability to sensitively monitor the temporal dynamics of (p)ppGpp abundance under diverse environmental conditions.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 8","pages":"e1011691"},"PeriodicalIF":3.7,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12373219/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144975698","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":"Rapid emergence of non-autonomous elements may stop P-element invasions in the absence of a piRNA-based host defence.","authors":"Matthew Beaumont, Divya Selvaraju, Riccardo Pianezza, Robert Kofler","doi":"10.1371/journal.pgen.1011649","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011649","url":null,"abstract":"<p><p>Transposable element (TE) invasions pose risks to both the TE and the host. All copies of a TE may be lost via genetic drift, or host populations may suffer fitness declines, potentially leading to extinction. By monitoring invasions of the P-element in experimental D. melanogaster populations for over 100 generations, we uncovered a novel risk for invading TEs. In two replicate populations, the P-element rapidly multiplied until a piRNA-based host defence emerged, leading to the plateauing of TE copy numbers. However, in one population (R2), P-element copy numbers stabilised at a significantly lower level, despite the absence of a piRNA-based host defence. We find that this stabilisation was likely driven by the propagation of non-autonomous insertions, characterised by internal-deletions, which out-competed the autonomous full-length insertions. Such a rapid proliferation of non-autonomous insertions could account for the high prevalence of P-element insertions with internal-deletions observed in natural D. melanogaster populations. Our work reveals that TEs may stochastically sabotage their own spread in populations due to the emergence of non-autonomous elements, rendering the establishment of a host defence unnecessary. The proliferation of non-autonomous elements may also lead into an evolutionary dead end, where affected populations are resistant to re-invasion (e.g. following recurrent horizontal transfer), yet are unable to infect other species due to a lack of autonomous insertions.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 8","pages":"e1011649"},"PeriodicalIF":3.7,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12393704/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144975682","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":"Characterization of eclosion hormone receptor function reveals differential hormonal control of ecdysis during Drosophila development.","authors":"Valeria Silva, Robert Scott, Paulina Guajardo, Haojiang Luan, Ruben Herzog, Benjamin H White, John Ewer","doi":"10.1371/journal.pgen.1011672","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011672","url":null,"abstract":"<p><p>Neuromodulators and peptide hormones play important roles in regulating animal behavior. A well-studied example is ecdysis, which is used by insects to shed their exoskeleton at the end of each molt. Ecdysis is initiated by Ecdysis Triggering Hormone (ETH) and Eclosion Hormone (EH), which interact via positive feedback to coordinate the sequence of behavioral and physiological changes that cause exoskeleton shedding. Whereas the cell types targeted by ETH are well characterized, those targeted by EH have remained largely unknown due to limited characterization of the EH receptor (EHR). A gene encoding an EHR has been described in the oriental fruit fly, B. dorsalis, and in the desert locust, Schistocerca gregaria. However, little is known in these species about its expression pattern and its precise role at ecdysis, and no other insect EHRs are known. Here we analyze CG10738, the Drosophila ortholog of the B. dorsalis gene encoding EHR, and show that expressing it in cells confers sensitivity to EH. In addition, mutations of CG10738 specifically disrupt ecdysis, phenocopying the knockout of the EH gene. Together, these results indicate that CG10738 encodes the Drosophila EHR. As in B. dorsalis, EHR is expressed in the ETH-producing Inka cells; in addition, it is expressed in many known targets of ETH, including the neurons responsible for the secretion of other ecdysis-related peptides, such as CCAP and EH itself. Our results from targeted knockdown and rescue experiments reveal that EHR is required for ecdysis in diverse cell types and that the role of EHR in different targets differs with developmental stage. Our findings indicate extensive convergence of EH and ETH signaling and provide an exemplar of the complex mechanisms by which hormones control animal behavior.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 8","pages":"e1011672"},"PeriodicalIF":3.7,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12393706/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144975684","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":"Deciphering the RNA-based regulation mechanism of the phage-encoded AbiF system in Clostridioides difficile.","authors":"Marion Saunier, Adeline Humbert, Victor Kreis, Johann Peltier, Arianna Tisba, Sylvie Auxilien, Marion Blum, Isabelle Caldelari, Jean-François Lucier, Joe Ueda, Daniel Gautheret, Claire Toffano-Nioche, Jessica Andreani, Louis-Charles Fortier, Olga Soutourina","doi":"10.1371/journal.pgen.1011831","DOIUrl":"10.1371/journal.pgen.1011831","url":null,"abstract":"<p><p>Clostridioides difficile is the major cause of nosocomial infections associated with antibiotic therapy. The severity of C. difficile infections increased worldwide with the emergence of hypervirulent strains, including 027 ribotype epidemic strains. Many aspects of C. difficile adaptation strategies during pathogenesis remain poorly understood. This pathogen thrives in gut communities that are rich in microbes and phages. To regulate horizontal transfer of genetic material during its infection cycle, C. difficile relies on diverse mechanisms. More specifically, CRISPR (clustered regularly interspaced short palindromic repeats)-Cas and Toxin-Antitoxin (TA) systems contribute to prophage maintenance, prevention of phage infection, and stress response. Abortive infection (Abi) systems can provide additional lines of anti-phage defense. RNAs have emerged as key components of these systems including CRISPR RNAs and antitoxin RNAs within type I and type III TA. We report here the identification of a new AbiF-like system within a prophage of the hypervirulent C. difficile strain R20291. It is associated with an Abi_2/AbiD/F protein family largely distributed in Bacillota and Pseudomonadota with structural links to ancestral Cas13 proteins at the origin of the RNA-targeting CRISPR-Cas13 systems. We demonstrated toxic activity of the AbiFCd protein in C. difficile and in Escherichia coli and negative regulation of the abiFCd expression by an associated non-coding RNA RCd22. RCd22 contains two conserved abiF motifs and is active both in cis and in trans to neutralize the toxin by direct RNA-protein interaction, similar to RNA antitoxin in type III TA. A mass spectrometry interactomics analysis of protein fractions from MS2-Affinity Purification coupled with RNA sequencing (MAPS) revealed the AbiFCd protein among the most enriched RCd22 partners in C. difficile. Structural modeling of the RNA-protein complex and mutagenesis analysis revealed key positions on both protein and RNA partners for this interaction and toxic activity. In summary, these findings provide valuable insights into the mechanisms of interaction between bacteria and phages, which are pertinent to the advancement of phage therapy, genome editing, epidemiological surveillance, and the formulation of novel therapeutic approaches.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 8","pages":"e1011831"},"PeriodicalIF":3.7,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12373285/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144884160","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":"Transcriptomic landscape and chromatin accessibility uncover pivotal regulators driving programmed larval-larval molting in the domesticated silkworm.","authors":"Yun Wang, Xin Yang, Junfeng Hong, Lingyi Li, Xia Ling, Liang Qiao, Ze Zhang, Wei Sun","doi":"10.1371/journal.pgen.1011837","DOIUrl":"10.1371/journal.pgen.1011837","url":null,"abstract":"<p><p>Insects undergo periodic ecdysis to shed their old chitinous exoskeleton and form a new cuticular layer. The steroid hormone 20-hydroxyecdysone (20E) is widely recognized as a central regulator of insect molting. Acting as a signaling molecule, 20E pulses orchestrate gene expression in a concentration- and time-dependent fashion. However, investigations into the transcriptomic and epigenomic alterations linked to dynamic 20E fluctuations remain limited. In this study, we explored the temporal dynamics of epidermal transcriptomes and genome-wide chromatin accessibility during the larval-larval molting cycle of the silkworm, Bombyx mori. Our results unveiled pronounced shifts in gene expression and chromatin architecture between early and late molting stages, correlating with ascending and descending 20E titers, respectively. Chromatin footprint analysis identified the Ecdysone receptor (EcR) and Grainy head (GRH) as early-stage regulators. Strikingly, during late molting phases, we uncovered a novel regulatory axis involving CCAAT/enhancer-binding protein (C/EBP) alongside the established factor Fushi-tarazu f1 (βFTZ-F1). Moreover, decline of the 20E titer triggers the expression of C/EBP, which subsequently regulates βFtz-f1 expression through promoter binding. Furthermore, epidermal-specific knockout of C/EBP and βFtz-f1 genes led to dysregulation of cuticular protein and chitin biosynthesis genes, impairing new cuticle formation. Collectively, our multi-omics dissection illuminates the dynamic regulatory circuitry coordinating epidermal remodeling and establishes a hierarchical transcriptional cascade governing cuticular renewal. These findings advance our understanding of hormone-driven developmental transitions in insects.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 8","pages":"e1011837"},"PeriodicalIF":3.7,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12380352/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144884161","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":"High-fat diet impairs intermediate-term memory by autophagic-lysosomal dysfunction in Drosophila.","authors":"Tong Yue, Minrui Jiang, Kotomi Onuki, Motoyuki Itoh, Ayako Tonoki","doi":"10.1371/journal.pgen.1011818","DOIUrl":"10.1371/journal.pgen.1011818","url":null,"abstract":"<p><p>High-fat diet (HFD) is considered a risk factor for age-related memory impairments such as Alzheimer's disease. However, how HFD affects memory formation remains unclear. In this study, we established a model of memory defects caused by HFD in Drosophila. Our results revealed that the HFD impaired intermediate-term memory (ITM), but not short-term memory (STM), produced by classical aversive olfactory conditioning, and decreased autophagic activity in the heads of the HFD-fed flies. Transient reduction in autophagic activity also impaired ITM, but not STM. Genetic enhancement of autophagic activity in neurons effectively restored ITM performance in the HFD-fed flies. Mechanistically, HFD impairs lysosomal function by downregulating the expression of lysosome-related genes, leading to impaired fusion of autophagosomes with lysosomes. These findings suggest that HFD impairs ITM by reducing autophagic activity and lysosomal dysfunction in the neurons.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 8","pages":"e1011818"},"PeriodicalIF":3.7,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12370196/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144876384","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":"Mutations mark cell lineages and sectors in flowers of a woody angiosperm.","authors":"Yilun Ji, Xiaonan Chen, Xiaohui Zhang, Wenjing Wang, Lan Xue, Yifan Zhong, Dacheng Tian, Sihai Yang, Long Wang, Milton Brian Traw, Ju Huang","doi":"10.1371/journal.pgen.1011829","DOIUrl":"10.1371/journal.pgen.1011829","url":null,"abstract":"<p><p>While radial sectors of flowers are likely to accumulate nested mutations, the distribution of natural somatic mutations across floral organs in dicot plants has not been studied previously. Here, we use next generation sequencing of 78 independent genome samples through sepals, petals, stamens, and carpel of two flowers to ask 1) whether radial sectors accumulate nested mutations, 2) whether carpels share de novo mutations with the radial parts, and 3) whether mutations can be used to estimate founder cell numbers in the floral anlagen. Mutations described seven sectors, each including a single petal and adjacent sepals, consistent with radial cell proliferation in the floral cup that predates the split of the sepal and petal cell populations. Mutations nested into two deep cell lineages that propagated through branching events and into every floral organ and unit of both flowers. Both carpels possessed two flower-wide de novo mutations, confirming that their genetic origin does not precede the floral anlagen. However, carpels possessed none of the sector marking mutations and therefore isolated genetically early in floral bud formation. Cell estimates of the flower-wide point mutations were most consistent with two cell floral initiation, one L1 and one L2, suggest a model of cell division in the floral anlagen. These observations represent the first genome-wide map of natural mutation distributions in a radially symmetric angiosperm flower.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 8","pages":"e1011829"},"PeriodicalIF":3.7,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12370204/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144876385","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":"RAB23 loss-of-function mutation causes context-dependent ciliopathy in Carpenter syndrome.","authors":"Wan Ying Leong, Wai Lam Tung, Andrew O M Wilkie, Catherine Hong Huan Hor","doi":"10.1371/journal.pgen.1011611","DOIUrl":"10.1371/journal.pgen.1011611","url":null,"abstract":"<p><p>The primary cilium is a signal transduction organelle whose dysfunction clinically causes ciliopathies in humans. RAB23 is a small GTPase known to regulate the Hedgehog signalling pathway and ciliary trafficking. Mutations of RAB23 in humans lead to Carpenter syndrome (CS), an autosomal recessive disorder clinically characterized by craniosynostosis, polysyndactyly, skeletal defects, obesity, and intellectual disability. Although the clinical features of CS bear some resemblance to those of ciliopathies, the exact relationship between the pathological manifestations of CS and the ciliary function of RAB23 remains ambiguous. Besides, the in vivo ciliary functions of RAB23 remain poorly characterised. Here, we demonstrate in vivo and in vitro Rab23 loss-of-function mutants modelling CS, including Rab23 conditional knockout (CKO) mouse mutants, CS patient-derived induced pluripotent stem cells (iPSCs), and zebrafish morphants. The Rab23-CKO mutants exhibit multiple developmental and phenotypical traits recapitulating the clinical features of human ciliopathies and CS, indicating a causal link between the loss of Rab23 and ciliopathy. In line with the ciliopathy-like phenotypes, all three different vertebrate mutant models consistently show a perturbation of primary cilia formation, intriguingly, in a context-dependent manner. Rab23-CKO mutants reveal cell-type specific ciliary abnormalities in chondrocytes, mouse embryonic fibroblasts, neural progenitor cells and neocortical neurons, but not in epithelial cells, cerebellar granule cells and hippocampus neurons. A profound reduction in ciliation frequency was observed specifically in neurons differentiated from CS patient iPSCs, whereas the patients' fibroblasts, iPSCs and neural progenitor cells maintained normal ciliation percentages but shortened cilia length. Furthermore, Rab23-KO neural progenitor cells show perturbed ciliation and desensitized to primary cilium-dependent activation of the Hedgehog signaling pathway. Collectively, these findings indicate that the absence of RAB23 causes dysfunctional primary cilia in a cell-type distinctive manner, which underlies the pathological manifestations of CS. Our findings present the first in vivo evidence validating the unique context-specific function of RAB23 in the primary cilium. Through the use of patient-derived iPSCs differentiated cells, we present direct evidence of primary cilia anomalies in CS, thereby confirming CS as a ciliopathy disorder.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 8","pages":"e1011611"},"PeriodicalIF":3.7,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12407540/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144876386","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":"The glycosyltransferase POGLUT1 regulates muscle stem cell development and maintenance in mice.","authors":"Soomin Cho, Emilia Servián-Morilla, Victoria Navarro, Beatriz Rodriguez-Gonzalez, Youxi Yuan, Raquel Cano, Arjun A Rambhiya, Radbod Darabi, Robert S Haltiwanger, Carmen Paradas, Hamed Jafar-Nejad","doi":"10.1371/journal.pgen.1011806","DOIUrl":"10.1371/journal.pgen.1011806","url":null,"abstract":"<p><p>Mutations in protein O-glucosyltransferase 1 (POGLUT1) cause a recessive limb-girdle muscular dystrophy (LGMDR21) with reduced satellite cell number and NOTCH1 signaling in adult patient muscles and impaired myogenic capacity of patient-derived muscle progenitors. However, the in vivo roles of POGLUT1 in the development, function, and maintenance of satellite cells are not well understood. Here, we show that conditional deletion of mouse Poglut1 in myogenic progenitors leads to early lethality, postnatal muscle growth defects, reduced Pax7 expression, abnormality in muscle extracellular matrix, and impaired muscle repair. Poglut1-deficient muscle progenitors exhibit reduced proliferation, enhanced differentiation, and accelerated fusion into myofibers. Inducible loss of Poglut1 in adult satellite cells leads to their loss of quiescence and precocious differentiation, and impairs muscle repair upon serial injury. Cell-based signaling assays and mass spectrometric analysis indicate that POGLUT1 is required for the activation of NOTCH1, NOTCH2, and NOTCH3 in myoblasts and that NOTCH3 is a target of POGLUT1 like NOTCH1 and NOTCH2. These observations provide insight into the roles of POGLUT1 in muscle development and repair and the pathophysiology of LGMDR21.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 8","pages":"e1011806"},"PeriodicalIF":3.7,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12373270/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144876396","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}