PLoS Genetics最新文献

{"title":"A mathematical framework for the quantitative analysis of genetic buffering.","authors":"Jim Karagiannis","doi":"10.1371/journal.pgen.1011730","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011730","url":null,"abstract":"<p><p>Genetic buffering plays a pivotal role in orchestrating the relationship between genotype and phenotype in outbred populations. While high-throughput screens have identified many instances of genetic buffering - through the detection of \"synthetic lethality\" or \"synthetic sickness\" - a formal and general method for its quantitative analysis across systems is lacking. In this report, an axiomatic mathematical framework that can be used to classify, quantify, and compare buffering relationships between genes is described. Importantly, this methodology employs a ratio scale as its basis, thereby permitting the definition of a novel neutrality model for gene interaction - the \"parallel\" model - which complements the commonly used \"product\" model. Evidence supporting the parallel model is provided through the statistical analysis of previously published yeast gene interaction data. This analysis reveals the consistent underestimation of double mutant fitness in strains carrying non-interacting query-array pairings (as predicted by the existence of \"parallel\" relationships between genes). Moreover, a model incorporating parallel neutrality in the determination of expected double mutant fitness largely corrects the underestimation. Finally, it is shown that simple extensions of this newly developed framework permit the unambiguous definition and classification of gene interactions in a formal, general, and mathematical way. Consequently, the concept of genetic buffering as first conceived by Leland Hartwell becomes a specific case within a comprehensive model of gene interaction.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 6","pages":"e1011730"},"PeriodicalIF":4.0,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144267735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of the SAF-A/HNRNPU SAP domain in X chromosome inactivation, nuclear dynamics, transcription, splicing, and cell proliferation.","authors":"Judith A Sharp, Emily Sparago, Rachael Thomas, Kaitlyn Alimenti, Wei Wang, Michael D Blower","doi":"10.1371/journal.pgen.1011719","DOIUrl":"10.1371/journal.pgen.1011719","url":null,"abstract":"<p><p>SAF-A/HNRNPU is conserved throughout vertebrates and has emerged as an important factor regulating a multitude of nuclear functions, including lncRNA localization, gene expression, and splicing. Here we show the SAF-A protein is highly dynamic and interacts with nascent transcripts as part of this dynamic movement. This finding revises current models of SAF-A: rather than being part of a static nuclear scaffold/matrix structure that acts as a stable tether between RNA and chromatin, SAF-A executes nuclear functions as a dynamic protein, suggesting contacts between SAF-A, RNA, and chromatin are more high turnover interactions than previously appreciated. SAF-A has several functional domains, including an N-terminal SAP domain that binds directly to DNA and RNA. Phosphorylation of SAP domain serines S14 and S26 is important for SAF-A localization and function during mitosis, however, whether these serines are involved in interphase functions of SAF-A is not known. In this study we tested for the role of the SAP domain, and SAP domain serines S14 and S26 in X chromosome inactivation, protein dynamics, gene expression, splicing, and cell proliferation. Here we show that the SAP domain, and SAP domain serines S14 and S26 are required to maintain XIST RNA localization and XIST-dependent histone modifications on the inactive X chromosome, to execute normal protein dynamics, and to maintain normal cell proliferation. In addition, we present evidence that a Xi localization signal resides in the SAP domain, enabling SAF-A to engage with the Xi compartment in a manner distinct from other nuclear territories. We found that the SAP domain is not required to maintain gene expression and plays only a minor role in mRNA splicing. We propose a model whereby dynamic phosphorylation of SAF-A serines S14 and S26 mediates rapid turnover of SAF-A interactions with nuclear structures during interphase. Our data suggest that different nuclear compartments may have distinct requirements for the SAF-A SAP domain to execute nuclear functions, a level of control that was not previously known.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 6","pages":"e1011719"},"PeriodicalIF":4.0,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12176297/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144267736","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":"Environmental data provide marginal benefit for predicting climate adaptation.","authors":"Forrest Li, Daniel J Gates, Edward S Buckler, Matthew B Hufford, Garrett M Janzen, Rubén Rellán-Álvarez, Fausto Rodríguez-Zapata, J Alberto Romero Navarro, Ruairidh J H Sawers, Samantha J Snodgrass, Kai Sonder, Martha C Willcox, Sarah J Hearne, Jeffrey Ross-Ibarra, Daniel E Runcie","doi":"10.1371/journal.pgen.1011714","DOIUrl":"10.1371/journal.pgen.1011714","url":null,"abstract":"<p><p>Climate change poses a major challenge for both natural and cultivated species. Genomic tools are increasingly used in both conservation and breeding to identify adaptive loci that can be used to guide management in future climates. Here, we study the utility of climate and genomic data for identifying promising alleles using common gardens of a large, geographically diverse sample of traditional maize varieties to evaluate multiple approaches. First, we used genotype data to predict environmental characteristics of germplasm collections to identify varieties that may be pre-adapted to target environments. Second, we used environmental GWAS (envGWAS) to identify loci associated with historical divergence along climatic gradients. Finally, we compared the value of environmental data and envGWAS-prioritized loci to genomic data for prioritizing traditional varieties. We find that maize yield traits are best predicted by genome-wide relatedness and population structure, and that incorporating envGWAS-identified variants or environment-of-origin data provide little additional predictive information. While our results suggest that environmental data provide limited benefit in predicting fitness-related phenotypes, environmental GWAS is nonetheless a potentially powerful approach to identify individual novel loci associated with adaptation, especially when coupled with high density genotyping.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 6","pages":"e1011714"},"PeriodicalIF":4.0,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12173371/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144259186","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":"Methylobacterium extorquens PA1 utilizes multiple strategies to maintain formaldehyde homeostasis during methylotrophic growth.","authors":"Zachary T Hying, Anya M Rushmer, Chin Yi Loh, Eric L Bruger, Jannell V Bazurto","doi":"10.1371/journal.pgen.1011736","DOIUrl":"10.1371/journal.pgen.1011736","url":null,"abstract":"<p><p>Metabolic homeostasis is a central organizing principle of physiology whereby dynamic processes work to maintain a balanced internal state. Highly reactive essential metabolites are ideally maintained at equilibrium to prevent cellular damage. In the facultative methylotrophic bacterium Methylobacterium extorquens PA1, the utilization of one-carbon growth substrates, including methanol, generates formaldehyde as an obligate intermediate. Formaldehyde is highly chemically reactive and capable of damaging various biomolecules, making formaldehyde homeostasis critical during methylotrophic growth. However, homeostatic mechanisms that govern formaldehyde balance, which is readily perturbed upon transitioning to methylotrophic growth substrates, have remained elusive. Here we describe how a formaldehyde-sensing protein EfgA, a formaldehyde-responsive MarR-like regulator TtmR, and lanthanide-mediated methylotrophy together impact formaldehyde balance and one-carbon metabolism more broadly when cells are transitioning to growth on formaldehyde-generating one-carbon sources. We found that cells lacking efgA or ttmR are unable to maintain formaldehyde balance during various carbon source transitions resulting in elevated extracellular formaldehyde concentrations and an extended lag phase. In strains lacking efgA, we showed that inflated intracellular formaldehyde pools were accompanied by decreased cell viability, while the loss of ttmR resulted in the loss of one-carbon metabolites to the extracellular space. Additionally, we found less severe formaldehyde imbalances in the presence of lanthanides, even in the absence of efgA and ttmR. This was partly due to the activation of exaF, a lanthanide-dependent alcohol dehydrogenase that served as an alternative formaldehyde-detoxifying system that lessened the necessity of ttmR for maintaining formaldehyde homeostasis. Overall, our data demonstrated that efgA has a primary role in formaldehyde homeostasis in modulating intracellular formaldehyde pools, while ttmR is secondary, preventing carbon loss to the extracellular space. These results led us to develop a model of formaldehyde homeostasis involving formaldehyde sensing, growth arrest, compartmentalization, and auxiliary detoxification systems. This work deepens our understanding of how physiological factors impact biological formaldehyde homeostasis during transient metabolic imbalances of this universal cellular toxin.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 6","pages":"e1011736"},"PeriodicalIF":4.0,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144259187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sodium azide mutagenesis induces a unique pattern of mutations.","authors":"Chaochih Liu, Giulia Frascarelli, Adrian O Stec, Shane Heinen, Li Lei, Skylar R Wyant, Erik Legg, Monika Spiller, Gary J Muehlbauer, Kevin P Smith, Justin C Fay, Peter L Morrell","doi":"10.1371/journal.pgen.1011634","DOIUrl":"10.1371/journal.pgen.1011634","url":null,"abstract":"<p><p>The nature and effect of mutations are of fundamental importance to the evolutionary process. The generation of mutations with mutagens has also played important roles in genetics. Applications of mutagens include dissecting the genetic basis of trait variation, inducing desirable traits in crops, and understanding the nature of genetic load. Previous studies of sodium azide-induced mutations have reported single nucleotide variants (SNVs) found in individual genes. To characterize the nature of mutations induced by sodium azide, we analyze whole-genome sequencing (WGS) of 11 barley lines derived from sodium azide mutagenesis, where all lines were selected for diminution of plant fitness owing to induced mutations. We contrast observed mutagen-induced variants with those found in standing variation in WGS of 13 barley landraces. Here, we report indels that are two orders of magnitude more abundant than expected based on nominal mutation rates. We found induced SNVs are very specific, with C → T changes occurring in a context followed by another C on the same strand (or the reverse complement). The codons most affected by the mutagen include the sodium azide-specific CC motif (or the reverse complement), resulting in a handful of amino acid changes and few stop codons. The specific nature of induced mutations suggests that mutagens could be chosen based on experimental goals. Sodium azide would not be ideal for gene knockouts but will create many missense mutations with more subtle effects on protein function.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 6","pages":"e1011634"},"PeriodicalIF":4.0,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12162104/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144217362","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":"Fitness consequences of sex chromosome aneuploidy in Drosophila melanogaster.","authors":"Elizabeth R Makovec, Caitlin C Kestell, Kayla K Janke, Ethan J Carter, Aaron P Ragsdale, Nathaniel P Sharp","doi":"10.1371/journal.pgen.1011703","DOIUrl":"10.1371/journal.pgen.1011703","url":null,"abstract":"<p><p>Of the array of spontaneous mutations that can occur, changes to chromosome number may have the greatest impact on the evolutionary potential of populations and the condition of affected individuals. Chromosomal nondisjunction resulting in aneuploidy is found across eukaryotes, but the consequences of such karyotypic variation have not been widely explored. In the fruit fly Drosophila melanogaster, aneuploid females with an XXY karyotype can arise through nondisjunction, inheriting a Y chromosome from their male parent. While the Y chromosome contains few genes, the large amount of heterochromatic DNA it contains can substantially alter genome-wide gene expression in females. We conducted a series of experiments to understand how sex chromosome aneuploidy alters key traits in affected females and their progeny. In the same genetic background, we also determined the rate at which this karyotype appears spontaneously and its standing frequency. We found that XXY females largely resembled XX females, but experienced size and fecundity benefits when receiving a male-transmitted Y chromosome. However, XYY males produced by aneuploid females experienced reduced viability, limiting the standing frequency of aneuploidy at mutation-selection equilibrium. Our findings demonstrate that aneuploid flies are not too rare in laboratory populations, but that the effects of this karyotypic diversity depend on sex and parent of origin.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 6","pages":"e1011703"},"PeriodicalIF":4.0,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12133181/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144217360","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":"HarmGR13 mediates myo-inositol taste perception in Helicoverpa armigera larvae.","authors":"Yu-Sheng Tan, Bao-Tong Mo, Guo-Cheng Li, Yu-Ruo Guo, Jian-Zhen Zhang, Chen-Zhu Wang","doi":"10.1371/journal.pgen.1011744","DOIUrl":"10.1371/journal.pgen.1011744","url":null,"abstract":"<p><p>Myo-inositol, a sugar alcohol produced by most plants, serves as a nutrient and feeding stimulant for many phytophagous insects. Inositol-sensitive taste sensilla have been characterized in many Lepidoptera larvae, but their molecular bases remain unclear. In this study, we determined the gustatory receptors (GRs) for myo-inositol in larva of Helicoverpa armigera, a worldwide crop pest. First, electrophysiological analyses revealed that medial sensilla styloconica strongly responded to myo-inositol and ribose, with weaker responses to xylose, and one GRN inside sensillum may mediate the response to these three chemicals. Based on phylogenetic analysis of sugar GRs of Lepidoptera insects and previous results on Bombyx mori, we then selected two candidate GRs, HarmGR13 and HarmGR11. Using CRISPR-Cas9, we generated knockout mutants for the two GR genes. Knocking out HarmGR13 abolished the responses of the sensilla to myo-inositol, ribose, and xylose, while knocking out HarmGR11 showed no changes. Behavioral assays confirmed that larvae of HarmGR13 homozygous mutant lost the feeding preference to myo-inositol which the wild-type larvae had. Further functional analysis with Xenopus oocytes expressing system and two-electrode voltage-clamping demonstrated that myo-inositol and ribose specifically induced concentration-dependent currents in HarmGR13-expressing oocytes. Structural predictions and molecular docking of HarmGR13 revealed three amino acid residues might be involved in ligand binding. Mutation of these residues resulted in loss of oocyte responses to myo-inositol and ribose. We reveal that HarmGR13 is a receptor that mediates the activity of the cells sensitive to inositol and ribose in larvae, providing new molecular targets for the strategy of regulating the feeding behavior of pests by modifying taste.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 6","pages":"e1011744"},"PeriodicalIF":4.0,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12165416/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144217361","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":"Left-right cortical interactions drive intracellular pattern formation in the ciliate Tetrahymena.","authors":"Chinkyu Lee, Ewa Joachimiak, Wolfgang Maier, Yu-Yang Jiang, Mireya Parra, Karl F Lechtreck, Eric S Cole, Jacek Gaertig","doi":"10.1371/journal.pgen.1011735","DOIUrl":"10.1371/journal.pgen.1011735","url":null,"abstract":"<p><p>In ciliates, cortical organelles, including ciliary arrays, are positioned at precise locations along two polarity axes: anterior-posterior and circumferential (lateral). We explored the poorly understood mechanism of circumferential patterning, which generates left-right asymmetry. The model ciliate Tetrahymena has a single anteriorly-located oral apparatus. During cell division, a single new oral apparatus forms near the equator of the parental cell and along the longitude of the parental organelle. Cells homozygous for hypoangular 1 (hpo1) alleles, assemble multiple oral apparatuses positioned either to the left or right flanking the normal oral longitude. Using comparative next-generation sequencing, we identified HPO1 as a gene encoding an ARMC9-like protein. Hpo1 colocalizes with the ciliary basal bodies, forming a bilateral concentration gradient, with the high point on the cell's right side and a sharp drop-off that marks the longitude at which oral development initiates on the ventral side. A second Hpo1 concentration drop-off is present on the dorsal surface, where it marks the position for development of a cryptic oral apparatus that forms in the janus mutants. Hpo1 acts bilaterally to exclude oral development from the cell's right side. Hpo1 interacts with the Beige-Beach domain protein Bcd1, a cell's left side-enriched factor, whose loss also confers multiple oral apparatuses on the ventral surface. A loss of both Hpo1 and Bcd1 is lethal and profoundly disrupts the positioning, organization and size of the forming oral apparatus (including its internal left-right polarity). We conclude that in ciliates, the circumferential patterning involves gradient-forming factors that are concentrated on either the cell's right or left side and that the two sides of the cortex interact to create boundary effects that induce, position and shape developing cortical organelles.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 6","pages":"e1011735"},"PeriodicalIF":4.0,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12151471/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144210024","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":"ciRS-7 expression is epigenetically regulated in cancer cells across human adenocarcinomas.","authors":"Thea P Paasch, Morten T Jarlstad Olesen, Juan L García-Rodríguez, Adrienne M Assmus, Robert A Fenton, Jørgen Kjems, Henrik Hager, Lasse S Kristensen","doi":"10.1371/journal.pgen.1011726","DOIUrl":"10.1371/journal.pgen.1011726","url":null,"abstract":"<p><p>Circular RNAs (circRNAs) constitute a large class of non-coding RNAs with gene regulatory capabilities, mainly through microRNA binding, a mechanism that has been linked to cancer development. The circRNA ciRS-7 (also known as CDR1as) is an interesting candidate as it harbors over 60 binding sites for miR-7, which is known to have tumor-suppressing properties. Here, we investigated the spatial expression patterns and epigenetic regulation of ciRS-7 across nine different adenocarcinomas originating from the colon, pancreas, ovary, endometrium, breast, stomach, bile duct, lung, and prostate. The study included primary patient samples and 18 different cell lines. ciRS-7 expression was analyzed using Reverse Transcription-quantitative PCR (RT-qPCR), single molecule in situ hybridization, and Nanostring nCounter, while epigenetic modifications were examined through bisulfite sequencing, Sensitive Melting Analysis after Real Time - Methylation Specific PCR (SMART-MSP), and chromatin immunoprecipitation. The functional relevance of epigenetic modifications was examined using DNA methyltransferase and histone deacetylase inhibitors. Across all adenocarcinomas, ciRS-7 was absent in the cancer cells in most of the primary tumor specimens, except for the breast tumors, while being expressed in the tumor microenvironment (TME). In line with this, ciRS-7 was not detected in most of the cell lines. Moreover, we demonstrated that DNA methylation and H3K9 acetylation, but not H3K27 methylation, are important epigenetic modifications that impact ciRS-7 expression. In conclusion, our data show that ciRS-7 is mainly expressed in the TME and is regulated through DNA methylation and histone acetylation across all major types of adenocarcinomas.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 6","pages":"e1011726"},"PeriodicalIF":4.0,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12162099/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144210022","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":"Ubinuclein 2 is essential for mouse development and functions in X chromosome inactivation.","authors":"Asun Monfort, Giulio Di Minin, Sarah Sting, Charles Etienne Dumeau, Peter Scambler, Anton Wutz","doi":"10.1371/journal.pgen.1011711","DOIUrl":"10.1371/journal.pgen.1011711","url":null,"abstract":"<p><p>The HIRA complex mediates deposition of histone H3.3 independent of replication. Its functions in gene regulation in mice remain to be fully understood. Here we analyze mutations of the HIRA complex genes Ubn1 and Ubn2. We observe that Ubn1 mutant mice of both sexes are viable and fertile. In contrast, mutation of Ubn2 causes embryonic lethality with variable penetrance and skewed sex ratio in favor of males. Combined Ubn1 and Ubn2 mutations cause embryonic lethality with complete penetrance, variable developmental arrest before turning, and reduced recovery of female embryos. Consistent with a female specific function of the HIRA complex, reanalysis of the Hira mutation during embryogenesis reveals that previously observed severe and mild phenotypic classes correspond to female and male sex. Mechanistically, we show that mutations of Ubn1, Ubn2, and Hira in mouse embryonic stem cells affect the initiation of X inactivation. Xist mediated gene silencing is impaired to increasing extent by Ubn1, Ubn2, Hira, and combined Ubn1 and Ubn2 mutations. We identify a failure of establishing histone H3 tri-methyl lysine 27 over X-linked genes after induction of Xist expression as earliest molecular defect, whereas deacetylation of lysine 27 by Xist remains largely unaffected by the loss of Ubinucleins. Our study thereby identifies a switch from histone H3 acetyl to tri-methyl lysine 27 at the initiation of X inactivation that depends on HIRA complex function.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 6","pages":"e1011711"},"PeriodicalIF":4.0,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12165345/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144210025","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}