PLoS Genetics最新文献

{"title":"Distinct cellular and junctional dynamics independently regulate the rotation and elongation of the embryonic gut in Drosophila.","authors":"Mikiko Inaki, Takamasa Higashi, Satoru Okuda, Kenji Matsuno","doi":"10.1371/journal.pgen.1011422","DOIUrl":"10.1371/journal.pgen.1011422","url":null,"abstract":"<p><p>Complex organ structures are formed with high reproducibility. To achieve such intricate morphologies, the responsible epithelium undergoes multiple simultaneous shape changes, such as elongation and folding. However, these changes have typically been assessed separately. In this study, we revealed how distinct shape changes are controlled during internal organ morphogenesis. The Drosophila embryonic hindgut undergoes left-right asymmetric rotation and anteroposterior elongation in a tissue-autonomous manner driven by cell sliding and convergent extension, respectively, in the hindgut epithelia. However, the regulation of these processes remains unclear. Through genetic analysis and live imaging, we demonstrated that cell sliding and convergent extension are independently regulated by Myosin1D and E-cadherin, and Par-3, respectively, whereas both require MyosinII activity. Using a mathematical model, we demonstrated that independently regulated cellular dynamics can simultaneously cause shape changes in a single mechanical system using anisotropic edge contraction. Our findings indicate that distinct cellular dynamics sharing a common apparatus can be independently and simultaneously controlled to form complex organ shapes. This suggests that such a mechanism may be a general strategy during complex tissue morphogenesis.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"20 10","pages":"e1011422"},"PeriodicalIF":4.0,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11486408/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142394563","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":"STAREG: Statistical replicability analysis of high throughput experiments with applications to spatial transcriptomic studies.","authors":"Yan Li, Xiang Zhou, Rui Chen, Xianyang Zhang, Hongyuan Cao","doi":"10.1371/journal.pgen.1011423","DOIUrl":"10.1371/journal.pgen.1011423","url":null,"abstract":"<p><p>Replicable signals from different yet conceptually related studies provide stronger scientific evidence and more powerful inference. We introduce STAREG, a statistical method for replicability analysis of high throughput experiments, and apply it to analyze spatial transcriptomic studies. STAREG uses summary statistics from multiple studies of high throughput experiments and models the the joint distribution of p-values accounting for the heterogeneity of different studies. It effectively controls the false discovery rate (FDR) and has higher power by information borrowing. Moreover, it provides different rankings of important genes. With the EM algorithm in combination with pool-adjacent-violator-algorithm (PAVA), STAREG is scalable to datasets with millions of genes without any tuning parameters. Analyzing two pairs of spatially resolved transcriptomic datasets, we are able to make biological discoveries that otherwise cannot be obtained by using existing methods.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"20 10","pages":"e1011423"},"PeriodicalIF":4.0,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11478871/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142373301","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 middle domain of Hsp104 can ensure substrates are functional after processing.","authors":"Hannah E Buchholz, Jane E Dorweiler, Sam Guereca, Brett T Wisniewski, James Shorter, Anita L Manogaran","doi":"10.1371/journal.pgen.1011424","DOIUrl":"10.1371/journal.pgen.1011424","url":null,"abstract":"<p><p>Molecular chaperones play a central role in protein disaggregation. However, the molecular determinants that regulate this process are poorly understood. Hsp104 is an AAA+ ATPase that disassembles stress granules and amyloids in yeast through collaboration with Hsp70 and Hsp40. In vitro studies show that Hsp104 processes different types of protein aggregates by partially translocating or threading polypeptides through the central pore of the hexamer. However, it is unclear how Hsp104 processing influences client protein function in vivo. The middle domain (MD) of Hsp104 regulates ATPase activity and interactions with Hsp70. Here, we tested how MD variants, Hsp104A503S and Hsp104A503V, process different protein aggregates. We establish that engineered MD variants fail to resolve stress granules but retain prion fragmentation activity required for prion propagation. Using the Sup35 prion protein, our in vitro and in vivo data indicate that the MD variants can disassemble Sup35 aggregates, but the disaggregated protein has reduced GTPase and translation termination activity. These results suggest that the middle domain can play a role in sensing certain substrates and plays an essential role in ensuring the processed protein is functional.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"20 10","pages":"e1011424"},"PeriodicalIF":4.0,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11478891/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142373302","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":"Yeast Nat4 regulates DNA damage checkpoint signaling through its N-terminal acetyltransferase activity on histone H4.","authors":"Mamantia Constantinou, Evelina Charidemou, Izge Shanlitourk, Katerina Strati, Antonis Kirmizis","doi":"10.1371/journal.pgen.1011433","DOIUrl":"10.1371/journal.pgen.1011433","url":null,"abstract":"<p><p>The DNA damage response (DDR) constitutes a vital cellular process that safeguards genome integrity. This biological process involves substantial alterations in chromatin structure, commonly orchestrated by epigenetic enzymes. Here, we show that the epigenetic modifier N-terminal acetyltransferase 4 (Nat4), known to acetylate the alpha-amino group of serine 1 on histones H4 and H2A, is implicated in the response to DNA damage in S. cerevisiae. Initially, we demonstrate that yeast cells lacking Nat4 have an increased sensitivity to DNA damage and accumulate more DNA breaks than wild-type cells. Accordingly, upon DNA damage, NAT4 gene expression is elevated, and the enzyme is specifically recruited at double-strand breaks. Delving deeper into its effects on the DNA damage signaling cascade, nat4-deleted cells exhibit lower levels of the damage-induced modification H2AS129ph (γH2A), accompanied by diminished binding of the checkpoint control protein Rad9 surrounding the double-strand break. Consistently, Mec1 kinase recruitment at double-strand breaks, critical for H2AS129ph deposition and Rad9 retention, is significantly impaired in nat4Δ cells. Consequently, Mec1-dependent phosphorylation of downstream effector kinase Rad53, indicative of DNA damage checkpoint activation, is reduced. Importantly, we found that the effects of Nat4 in regulating the checkpoint signaling cascade are mediated by its N-terminal acetyltransferase activity targeted specifically towards histone H4. Overall, this study points towards a novel functional link between histone N-terminal acetyltransferase Nat4 and the DDR, associating a new histone-modifying activity in the maintenance of genome integrity.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"20 10","pages":"e1011433"},"PeriodicalIF":4.0,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11472955/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142367056","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":"C1-FDX is required for the assembly of mitochondrial complex I and subcomplexes of complex V in Arabidopsis.","authors":"Baoyin Chen, Junjun Wang, Manna Huang, Yuanye Gui, Qingqing Wei, Le Wang, Bao-Cai Tan","doi":"10.1371/journal.pgen.1011419","DOIUrl":"10.1371/journal.pgen.1011419","url":null,"abstract":"<p><p>C1-FDX (Complex I-ferredoxin) has been defined as a component of CI in a ferredoxin bridge in Arabidopsis mitochondria. However, its full function remains to be addressed. We created two c1-fdx mutants in Arabidopsis using the CRISPR-Cas9 methodology. The mutants show delayed seed germination. Over-expression of C1-FDX rescues the phenotype. Molecular analyses showed that loss of the C1-FDX function decreases the abundance and activity of both CI and subcomplexes of CV. In contrast, the over-expression of C1-FDX-GFP enhances the CI* (a sub-complex of CI) and CV assembly. Immunodetection reveals that the stoichiometric ratio of the α:β subunits in the F1 module of CV is altered in the c1-fdx mutant. In the complemented mutants, C1-FDX-GFP was found to be associated with the F' and α/β sub-complexes of CV. Protein interaction assays showed that C1-FDX could interact with the β, γ, δ, and ε subunits of the F1 module, indicating that C1-FDX, a structural component of CI, also functions as an assembly factor in the assembly of F' and α/β sub-complexes of CV. These results reveal a new role of C1-FDX in the CI and CV assembly and seed germination in Arabidopsis.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"20 10","pages":"e1011419"},"PeriodicalIF":4.0,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11446459/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142367055","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":"Prioritizing disease-related rare variants by integrating gene expression data.","authors":"Hanmin Guo, Alexander Eckehart Urban, Wing Hung Wong","doi":"10.1371/journal.pgen.1011412","DOIUrl":"10.1371/journal.pgen.1011412","url":null,"abstract":"<p><p>Rare variants, comprising the vast majority of human genetic variations, are likely to have more deleterious impact in the context of human diseases compared to common variants. Here we present carrier statistic, a statistical framework to prioritize disease-related rare variants by integrating gene expression data. By quantifying the impact of rare variants on gene expression, carrier statistic can prioritize those rare variants that have large functional consequence in the patients. Through simulation studies and analyzing real multi-omics dataset, we demonstrated that carrier statistic is applicable in studies with limited sample size (a few hundreds) and achieves substantially higher sensitivity than existing rare variants association methods. Application to Alzheimer's disease reveals 16 rare variants within 15 genes with extreme carrier statistics. We also found strong excess of rare variants among the top prioritized genes in patients compared to that in healthy individuals. The carrier statistic method can be applied to various rare variant types and is adaptable to other omics data modalities, offering a powerful tool for investigating the molecular mechanisms underlying complex diseases.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"20 9","pages":"e1011412"},"PeriodicalIF":4.0,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11466430/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330661","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":"Hypopituitarism in Sox3 null mutants correlates with altered NG2-glia in the median eminence and is influenced by aspirin and gut microbiota.","authors":"Christophe Galichet, Karine Rizzoti, Robin Lovell-Badge","doi":"10.1371/journal.pgen.1011395","DOIUrl":"10.1371/journal.pgen.1011395","url":null,"abstract":"<p><p>The median eminence (ME), located at the base of the hypothalamus, is an essential centre of information exchange between the brain and the pituitary. We and others previously showed that mutations and duplications affecting the transcription factor SOX3/Sox3 result in hypopituitarism, and this is likely of hypothalamic origin. We demonstrate here that the absence of Sox3 predominantly affects the ME with phenotypes that first occur in juvenile animals, despite the embryonic onset of SOX3 expression. In the pituitary, reduction in hormone levels correlates with a lack of endocrine cell maturation. In parallel, ME NG2-glia renewal and oligodendrocytic differentiation potential are affected. We further show that low-dose aspirin treatment, which is known to affect NG2-glia, or changes in gut microbiota, rescue both proliferative defects and hypopituitarism in Sox3 mutants. Our study highlights a central role of NG2-glia for ME function during a transitional period of post-natal development and indicates their sensitivity to extrinsic signals.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"20 9","pages":"e1011395"},"PeriodicalIF":4.0,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11426531/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330659","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":"Multiple independent losses of crossover interference during yeast evolutionary history.","authors":"Abhishek Dutta, Fabien Dutreux, Marion Garin, Claudia Caradec, Anne Friedrich, Gauthier Brach, Pia Thiele, Maxime Gaudin, Bertrand Llorente, Joseph Schacherer","doi":"10.1371/journal.pgen.1011426","DOIUrl":"10.1371/journal.pgen.1011426","url":null,"abstract":"<p><p>Meiotic recombination is essential for the accurate chromosome segregation and the generation of genetic diversity through crossover and gene conversion events. Although this process has been studied extensively in a few selected model species, understanding how its properties vary across species remains limited. For instance, the ancestral ZMM pathway that generates interference-dependent crossovers has undergone multiple losses throughout evolution, suggesting variations in the regulation of crossover formation. In this context, we first characterized the meiotic recombination landscape and properties of the Kluyveromyces lactis budding yeast. We then conducted a comprehensive analysis of 29,151 recombination events (19, 212 COs and 9, 939 NCOs) spanning 577 meioses in the five budding yeast species Saccharomyces cerevisiae, Saccharomyces paradoxus, Lachancea kluyveri, Lachancea waltii and K. lactis. Eventually, we found that the Saccharomyces yeasts displayed higher recombination rates compared to the non-Saccharomyces yeasts. In addition, bona fide crossover interference and associated crossover homeostasis were detected in the Saccharomyces species only, adding L. kluyveri and K. lactis to the list of budding yeast species that lost crossover interference. Finally, recombination hotspots, although highly conserved within the Saccharomyces yeasts are not conserved beyond the Saccharomyces genus. Overall, these results highlight great variability in the recombination landscape and properties through budding yeasts evolution.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"20 9","pages":"e1011426"},"PeriodicalIF":4.0,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11460703/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330660","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":"Human cells contain myriad excised linear intron RNAs with links to gene regulation and potential utility as biomarkers.","authors":"Jun Yao, Hengyi Xu, Elizabeth A Ferrick-Kiddie, Ryan M Nottingham, Douglas C Wu, Manuel Ares, Alan M Lambowitz","doi":"10.1371/journal.pgen.1011416","DOIUrl":"10.1371/journal.pgen.1011416","url":null,"abstract":"<p><p>A previous study using Thermostable Group II Intron Reverse Transcriptase sequencing (TGIRT-seq) found human plasma contains short (≤300 nt) structured full-length excised linear intron (FLEXI) RNAs with potential to serve as blood-based biomarkers. Here, TGIRT-seq identified >9,000 different FLEXI RNAs in human cell lines, including relatively abundant FLEXIs with cell-type-specific expression patterns. Analysis of public CLIP-seq datasets identified 126 RNA-binding proteins (RBPs) that have binding sites within the region corresponding to the FLEXI or overlapping FLEXI splice sites in pre-mRNAs, including 53 RBPs with binding sites for ≥30 different FLEXIs. These included splicing factors, transcription factors, a chromatin remodeling protein, cellular growth regulators, and proteins with cytoplasmic functions. Analysis of ENCODE datasets identified subsets of these RBPs whose knockdown impacted FLEXI host gene mRNA levels or proximate alternative splicing, indicating functional interactions. Hierarchical clustering identified six subsets of RBPs whose FLEXI binding sites were co-enriched in six subsets of functionally related host genes: AGO1-4 and DICER, including but not limited to agotrons or mirtron pre-miRNAs; DKC1, NOLC1, SMNDC1, and AATF (Apoptosis Antagonizing Transcription Factor), including but not limited to snoRNA-encoding FLEXIs; two subsets of alternative splicing factors; and two subsets that included RBPs with cytoplasmic functions (e.g., LARP4, PABPC4, METAP2, and ZNF622) together with regulatory proteins. Cell fractionation experiments showed cytoplasmic enrichment of FLEXI RNAs with binding sites for RBPs with cytoplasmic functions. The subsets of host genes encoding FLEXIs with binding sites for different subsets of RBPs were co-enriched with non-FLEXI other short and long introns with binding sites for the same RBPs, suggesting overarching mechanisms for coordinately regulating expression of functionally related genes. Our findings identify FLEXIs as a previously unrecognized large class of cellular RNAs and provide a comprehensive roadmap for further analyzing their biological functions and the relationship of their RBPs to cellular regulatory mechanisms.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"20 9","pages":"e1011416"},"PeriodicalIF":4.0,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11460701/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330658","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":"NEMF mutations in mice illustrate how Importin-β specific nuclear transport defects recapitulate neurodegenerative disease hallmarks.","authors":"Jonathan Plessis-Belair, Kathryn Ravano, Ellen Han, Aubrey Janniello, Catalina Molina, Roger B Sher","doi":"10.1371/journal.pgen.1011411","DOIUrl":"10.1371/journal.pgen.1011411","url":null,"abstract":"<p><p>Pathological disruption of Nucleocytoplasmic Transport (NCT), such as the mis-localization of nuclear pore complex proteins (Nups), nuclear transport receptors, Ran-GTPase, and RanGAP1, are seen in both animal models and in familial and sporadic forms of amyotrophic lateral sclerosis (ALS), frontal temporal dementia and frontal temporal lobar degeneration (FTDFTLD), and Alzheimer's and Alzheimer's Related Dementias (AD/ADRD). However, the question of whether these alterations represent a primary cause, or a downstream consequence of disease is unclear, and what upstream factors may account for these defects are unknown. Here, we report four key findings that shed light on the upstream causal role of Importin-β-specific nuclear transport defects in disease onset. First, taking advantage of two novel mouse models of NEMF neurodegeneration (NemfR86S and NemfR487G) that recapitulate many cellular and biochemical aspects of neurodegenerative diseases, we find an Importin-β-specific nuclear import block. Second, we observe cytoplasmic mis-localization and aggregation of multiple proteins implicated in the pathogenesis of ALS/FTD and AD/ADRD, including TDP43, Importin-β, RanGap1, and Ran. These findings are further supported by a pathological interaction between Importin-β and the mutant NEMFR86S protein in cytoplasmic accumulations. Third, we identify similar transcriptional dysregulation in key genes associated with neurodegenerative disease. Lastly, we show that even transient pharmaceutical inhibition of Importin-β in both mouse and human neuronal and non-neuronal cells induces key proteinopathies and transcriptional alterations seen in our mouse models and in neurodegeneration. Our convergent results between mouse and human neuronal and non-neuronal cellular biology provide mechanistic evidence that many of the mis-localized proteins and dysregulated transcriptional events seen in multiple neurodegenerative diseases may in fact arise primarily from a primary upstream defect in Importin- β nuclear import. These findings have critical implications for investigating how sporadic forms of neurodegeneration may arise from presently unidentified genetic and environmental perturbations in Importin-β function.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"20 9","pages":"e1011411"},"PeriodicalIF":4.0,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11449308/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142308874","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}