PLoS Genetics最新文献

{"title":"Conserved chromatin regulators control the transcriptional immune response to intracellular pathogens in Caenorhabditis elegans.","authors":"Eillen Tecle, Paaramitha Warushavithana, Samuel Li, Michael J Blanchard, Crystal B Chhan, Theresa Bui, Ryan S Underwood, Malina A Bakowski, Emily R Troemel, Vladimir Lažetić","doi":"10.1371/journal.pgen.1011444","DOIUrl":"10.1371/journal.pgen.1011444","url":null,"abstract":"<p><p>Robust transcriptional responses are critical for defense against infection. However, unrestrained immune responses can cause negative impacts such as damaging inflammation and slowed development. Here, we find that a class of transcriptional regulators previously associated with regulation of development in Caenorhabditis elegans, is also involved in repressing immune responses. Specifically, through forward genetics, we find that loss of lin-15B leads to constitutive expression of Intracellular Pathogen Response (IPR) genes. lin-15B encodes a transcriptional repressor with a conserved THAP domain that is associated with the DRM chromatin remodeling complex that regulates C. elegans development. We show that lin-15B mutants have increased resistance to natural intracellular pathogens, and the induction of IPR genes in lin-15B mutants relies on the MES-4 histone methyltransferase. We extend our analyses to other DRM and NuRD chromatin remodeling factors, as well as SUMOylation histone modifiers, showing that a broad range of chromatin-related factors can repress IPR gene expression. Altogether these findings suggest that conserved chromatin regulators may facilitate development in part by repressing damaging immune responses against intracellular pathogens.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 4","pages":"e1011444"},"PeriodicalIF":4.0,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11975079/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803943","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":"PPDPF is not a key regulator of human pancreas development.","authors":"Markus Breunig, Meike Hohwieler, Jasmin Haderspeck, Felix von Zweydorf, Natalie Hauff, Lino-Pascal Pasquini, Christoph Wiegreffe, Eleni Zimmer, Medhanie A Mulaw, Cécile Julier, Eric Simon, Christian Johannes Gloeckner, Stefan Liebau, Alexander Kleger","doi":"10.1371/journal.pgen.1011657","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011657","url":null,"abstract":"<p><p>Given their capability to differentiate into each cell type of the human body, human pluripotent stem cells (hPSCs) provide a unique platform for developmental studies. In the current study, we employed this cell system to understand the role of pancreatic progenitor differentiation and proliferation factor (PPDPF), a protein that has been little explored so far. While the zebrafish orthologue exdpf is essential for exocrine pancreas specification, its importance for mammalian and human development has not been studied yet. We implemented a four times CRISPR/Cas9 nicking approach to knockout PPDPF in human embryonic stem cells (hESCs) and differentiated PPDPFKO/KO and PPDPFWT/WT cells towards the pancreatic lineage. In contrast to data obtained from zebrafish, a very modest effect of the knockout was observed in the development of pancreatic progenitors in vitro, not affecting lineage specification upon orthotopic transplantation in vivo. The modest effect is in line with the finding that genetic variants near PPDPF are associated with random glucose levels in humans, but not with type 2 diabetes risk, supporting that dysregulation of this gene may only result in minor alterations of glycaemic balance in humans. In addition, PPDPF is less organ- and cell type specifically expressed in higher vertebrates and its so far reported functions appear highly context-dependent.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 4","pages":"e1011657"},"PeriodicalIF":4.0,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143804213","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":"Spindle integrity is regulated by a phospho-dependent interaction between the Ndc80 and Dam1 kinetochore complexes.","authors":"Christian R Nelson, Darren R Mallett, Sue Biggins","doi":"10.1371/journal.pgen.1011645","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011645","url":null,"abstract":"<p><p>Faithful chromosome segregation depends upon kinetochores, large protein complexes that anchor chromosomes to dynamic microtubules, allowing for their movement at anaphase. Critical microtubule-coupling components of the budding yeast kinetochore, the Dam1 (Dam1c) and Ndc80 (Ndc80c) complexes, work cooperatively to ensure that kinetochores track with the plus-ends of microtubules. Additionally, the Dam1 complex plays a distinct role in ensuring the integrity of the mitotic spindle. However, the events required to orchestrate these diverse functions of Dam1c remain unclear. To identify regulatory events on kinetochores, we performed phosphoproteomics on purified kinetochore proteins and identified many previously unknown phosphorylation events. We demonstrate that Ndc80 is phosphorylated at Thr-248 and Thr-252 to promote the interaction between Ndc80 and the Dam1c. The phosphorylation of T248 is cell cycle regulated and depends on Mps1. Ndc80 phosphorylation at T248 and T252 does not appear to regulate kinetochore function and instead contributes to Dam1c localization to the anaphase spindle. A ndc80 phospho-deficient mutant exhibited a genetic interaction and altered spindle morphology when combined with dam1 mutant alleles. Taken together, we propose that Mps1-dependent phosphorylation of Ndc80 at T248 and T252 is removed at anaphase to allow Dam1c to help organize and stabilize the spindle.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 4","pages":"e1011645"},"PeriodicalIF":4.0,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143784614","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":"ClpP2 proteasomes and SpxA1 determine Listeria monocytogenes tartrolon B hyper-resistance.","authors":"Tim Engelgeh, Sabrina Wamp, Patricia Rothe, Jennifer Herrmann, Martin A Fischer, Rolf Müller, Sven Halbedel","doi":"10.1371/journal.pgen.1011621","DOIUrl":"10.1371/journal.pgen.1011621","url":null,"abstract":"<p><p>The foodborne bacterium Listeria monocytogenes is transmitted to humans from various environmental sources through consumption of contaminated plant and animal-based food. L. monocytogenes uses ATP-binding cassette (ABC)-type drug transporters to resist antimicrobial compounds produced by competitors co-residing in its environmental reservoirs. We have shown previously that the TimAB transporter confers resistance of L. monocytogenes to tartrolon B, a boron containing macrodiolide produced by myxo- and proteobacterial species. Tartrolon B acts as a potassium ionophore and is sensed by TimR, the transcriptional repressor of timABR operon. We here have isolated tartrolon B resistant suppressor mutations outside the timABR locus. These mutations inactivated the clpP2 gene, which encodes the main proteolytic component of house-keeping Clp proteases. Deletion of clpP2 impaired growth and virulence but caused tartrolon B hyper-resistance. This phenotype was timAB-dependent, but neither production nor degradation of TimAB was affected upon clpP2 inactivation. Combinatorial deletions of the genes encoding the three Clp ATPases showed that ClpCP2 and ClpXP2 proteasomes jointly promote tartrolon B hyper-resistance. Genetic follow-up experiments identified the ClpP2 substrate and transcription factor SpxA1 and its protease adaptor YjbH as further tartrolon B resistance determinants. SpxA1 activates transcription of the cydABCD operon encoding cytochrome oxidase and in accordance with this transposon mutants with impaired cytochrome oxidase function were depleted from a transposon mutant library during tartrolon B exposure. Our work demonstrates novel roles of Clp proteasomes, SpxA1 and cytochrome oxidase CydAB in the resistance against compounds dissipating transmembrane ion gradients and helps to better understand the genetic and chemical basis of the manifold ecological interactions of an important human pathogen in its natural ecologic niches.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 4","pages":"e1011621"},"PeriodicalIF":4.0,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11970672/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143784612","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":"A phage-encoded counter-defense inhibits an NAD-degrading anti-phage defense system.","authors":"Christian L Loyo, Alan D Grossman","doi":"10.1371/journal.pgen.1011551","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011551","url":null,"abstract":"<p><p>Bacteria contain a diverse array of genes that provide defense against predation by phages. Anti-phage defense genes are frequently located on mobile genetic elements and spread through horizontal gene transfer. Despite the many anti-phage defense systems that have been identified, less is known about how phages overcome the defenses employed by bacteria. The integrative and conjugative element ICEBs1 in Bacillus subtilis contains a gene, spbK, that confers defense against the temperate phage SPβ through an abortive infection mechanism. Using genetic and biochemical analyses, we found that SpbK is an NADase that is activated by binding to the SPβ phage portal protein YonE. The presence of YonE stimulates NADase activity of the TIR domain of SpbK and causes cell death. We also found that the SPβ-like phage Φ3T has a counter-defense gene that prevents SpbK-mediated abortive infection and enables the phage to produce viable progeny, even in cells expressing spbK. We made SPβ-Φ3T hybrid phages that were resistant to SpbK-mediated defense and identified a single gene in Φ3T (phi3T_120, now called nip for NADase inhibitor from phage) that was both necessary and sufficient to block SpbK-mediated anti-phage defense. We found that Nip binds to the TIR (NADase) domain of SpbK and inhibits NADase activity. Our results provide insight into how phages overcome bacterial immunity by inhibiting enzymatic activity of an anti-phage defense protein.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 4","pages":"e1011551"},"PeriodicalIF":4.0,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143774559","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":"Identification of modifier gene variants overrepresented in familial hypomagnesemia with hypercalciuria and nephrocalcinosis patients with a more aggressive renal phenotype.","authors":"Monica Vall-Palomar, Julieta Torchia, Jordi Morata, Monica Durán, Raul Tonda, Mireia Ferrer, Alex Sánchez, Gerard Cantero-Recasens, Gema Ariceta, Anna Meseguer, Cristina Martinez","doi":"10.1371/journal.pgen.1011568","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011568","url":null,"abstract":"<p><p>Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is an ultra-rare autosomal recessive renal tubular disease with an incidence of <1/1.000.000 individuals, caused by loss-of-function mutations in CLDN16 and CLDN19. Our study includes a unique cohort representing all known FHHNC patients in Spain, with 90% harbouring mutations in CLDN19. Of these, 70% carry the p.G20D mutation in homozygosis. Despite this high genetic homogeneity, our FHHNC cohort display a high phenotypic variability, even among siblings harbouring identical mutations. Patients were stratified at the extremes of the renal phenotype according to their estimated glomerular filtration rate annual decline and subjected to whole exome sequencing (WES) aiming to find candidate phenotype-modifier genes. Initial statistical analysis by SKAT-O identified numerous variants, which were then filtered based on P-value <0.01 and kidney expression. A thorough prioritization strategy was then applied by an exhaustive disease knowledge-driven exploitation of data from public databases (Human Protein Atlas, GWAS catalog, GTEx) to further refine candidate genes. Odds ratios were also calculated to identify potential risk variants. This analysis pipeline suggested several gene variants associated with a higher risk of developing a more aggressive renal phenotype. While these findings hint at the existence of genetic modifiers in FHHNC, further research is needed to confirm their role and potential clinical significance. Clinical decisions should not be based on these preliminary findings, and additional cohorts should be studied to validate and expand upon our results. This exploratory study provides a foundation for future investigations into the genetic factors influencing FHHNC progression and may contribute to our understanding of the disease's variable expressivity potentially enabling the implementation of more tailored therapeutic strategies.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 4","pages":"e1011568"},"PeriodicalIF":4.0,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143774563","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":"A Rfa1-MN-based system reveals new factors involved in the rescue of broken replication forks.","authors":"Ana Amiama-Roig, Marta Barrientos-Moreno, Esther Cruz-Zambrano, Luz M López-Ruiz, Román González-Prieto, Gabriel Ríos-Orelogio, Félix Prado","doi":"10.1371/journal.pgen.1011405","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011405","url":null,"abstract":"<p><p>The integrity of the replication forks is essential for an accurate and timely completion of genome duplication. However, little is known about how cells deal with broken replication forks. We have generated in yeast a system based on a chimera of the largest subunit of the ssDNA binding complex RPA fused to the micrococcal nuclease (Rfa1-MN) to induce double-strand breaks (DSBs) at replication forks and searched for mutants affected in their repair. Our results show that the core homologous recombination (HR) proteins involved in the formation of the ssDNA/Rad51 filament are essential for the repair of DSBs at forks, whereas non-homologous end joining plays no role. Apart from the endonucleases Mus81 and Yen1, the repair process employs fork-associated HR factors, break-induced replication (BIR)-associated factors and replisome components involved in sister chromatid cohesion and fork stability, pointing to replication fork restart by BIR followed by fork restoration. Notably, we also found factors controlling the length of G1, suggesting that a minimal number of active origins facilitates the repair by converging forks. Our study has also revealed a requirement for checkpoint functions, including the synthesis of Dun1-mediated dNTPs. Finally, our screening revealed minimal impact from the loss of chromatin factors, suggesting that the partially disassembled nucleosome structure at the replication fork facilitates the accessibility of the repair machinery. In conclusion, this study provides an overview of the factors and mechanisms that cooperate to repair broken forks.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 4","pages":"e1011405"},"PeriodicalIF":4.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143765545","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":"Correction: Histone variant H2A.Z is needed for efficient transcription-coupled NER and genome integrity in UV challenged yeast cells.","authors":"Hélène Gaillard, Toni Ciudad, Andrés Aguilera, Ralf E Wellinger","doi":"10.1371/journal.pgen.1011646","DOIUrl":"10.1371/journal.pgen.1011646","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.1371/journal.pgen.1011300.].</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 4","pages":"e1011646"},"PeriodicalIF":4.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11960920/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143765557","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":"Generation of prostate cancer assembloids modeling the patient-specific tumor microenvironment.","authors":"Juhee Lee, Yunhee Kim, Cheol Lee, Seong Soo Jeon, Hae Seo, Jongwon Lee, Jungmin Choi, Minyong Kang, Eunjee Kim, Kunyoo Shin","doi":"10.1371/journal.pgen.1011652","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011652","url":null,"abstract":"<p><p>Prostate cancer (PC) is the most frequently diagnosed malignancy among men and contributes significantly to cancer-related mortality. While recent advances in in vitro PC modeling systems have been made, there remains a lack of robust preclinical models that faithfully recapitulate the genetic and phenotypic characteristics across various PC subtypes-from localized PC (LPC) to castration-resistant PC (CRPC)-along with associated stromal cells. Here, we established human PC assembloids from LPC and CRPC tissue by reconstituting tumor organoids with corresponding cancer-associated fibroblasts (CAFs), thereby incorporating aspects of the tumor microenvironment (TME). Established PC organoids exhibited high concordance in genomic landscape with parental tumors, and the tumor assembloids showed a higher degree of phenotypic similarity to parental tumors compared to tumor organoids without CAFs. PC assembloids displayed increased proliferation and reduced sensitivity to anti-cancer treatments, indicating that PC assembloids are potent tools for understanding PC biology, investigating interaction between tumor and CAFs, and identifying personalized therapeutic targets.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 3","pages":"e1011652"},"PeriodicalIF":4.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143755294","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":"Parental germline mosaicism in genome-wide phased de novo variants: Recurrence risk assessment and implications for precision genetic counselling.","authors":"François Lecoquierre, Nathalie Drouot, Sophie Coutant, Olivier Quenez, Steeve Fourneaux, Fanny Jumeau, Nathalie Rives, Françoise Charbonnier, Céline Derambure, Anne Boland, Robert Olaso, Vincent Meyer, Jean-François Deleuze, Alice Goldenberg, Anne-Marie Guerrot, Camille Charbonnier, Gaël Nicolas","doi":"10.1371/journal.pgen.1011651","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011651","url":null,"abstract":"<p><p>De novo mutations (DNMs) have a significant impact on human health, notably through their contribution to developmental disorders. DNMs occur in both paternal and maternal germlines via diverse mechanisms, including parental early embryonic mosaicism, at high recurrence risk for subsequent pregnancies through germline mosaicism. This phenomenon has been studied mostly on isolated pathogenic variants, but its contribution to genome-wide phased variants in individual genomes is underexplored. We aimed to categorize DNMs and their recurrence risk by detecting and phasing a large set of DNMs via short- and long-read genome sequencing followed by systematic deep sequencing of parental blood and sperm DNA. We detected an average of 85.6 DNM per trio (n=5 trios), with an expected paternal bias of 80%. Targeted resequencing of parental blood and sperm (depth>5000x) revealed 20/334 parental germline mosaics (2-5 per trio) with variant allele fractions (VAFs) ranging from 0.24% to 14.7%, including 7 that were detected in paternal sperm exclusively (1-2 per trio). Owing to paternal bias, maternally phased variants were 3.4x more likely to be mosaic in blood. VAF in sperm samples was used as an indicator for the risk of recurrence of paternally phased DNM. Fourteen variants (out of 244, 5.7%) exhibited detectable sperm mosaicism, while the remaining 230 showed no evidence of mosaicism. Sperm sequencing therefore enabled a precise quantification of the recurrence risk of most individual DNMs. We predict that the use of long-read genome sequencing in genomic medicine will enable the critical step of variant phasing, improving the genetic counselling of rare diseases mediated by DNMs.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 3","pages":"e1011651"},"PeriodicalIF":4.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143755317","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}