PLoS Genetics最新文献

{"title":"Evolution of canonical circadian clock genes underlies unique sleep strategies of marine mammals for secondary aquatic adaptation.","authors":"Daiqing Yin, Zhaomin Zhong, Fan Zeng, Zhikang Xu, Jing Li, Wenhua Ren, Guang Yang, Han Wang, Shixia Xu","doi":"10.1371/journal.pgen.1011598","DOIUrl":"10.1371/journal.pgen.1011598","url":null,"abstract":"<p><p>To satisfy the needs of sleeping underwater, marine mammals, including cetaceans, sirenians, and pinnipeds, have evolved an unusual form of sleep, known as unihemispheric slow-wave sleep (USWS), in which one brain hemisphere is asleep while the other is awake. All aquatic cetaceans have only evolved USWS without rapid eye movement (REM) sleep, whereas aquatic sirenians and amphibious pinnipeds display both bihemispheric slow-wave sleep (BSWS) and USWS, as well as REM sleep. However, the molecular genetic changes underlying USWS remain unknown. The present study investigated the evolution of eight canonical circadian genes and found that positive selection occurred mainly within cetacean lineages. Furthermore, convergent evolution was observed in lineages with USWS at three circadian clock genes. Remarkably, in vitro assays showed that cetacean-specific mutations increased the nuclear localization of zebrafish clocka, and enhanced the transcriptional activation activity of Clocka and Bmal1a. In vivo, transcriptome analysis showed that the overexpression of the cetacean-specific mutant clocka (clocka-mut) caused the upregulation of the wakefulness-promoting glutamatergic genes and the differential expression of multiple genes associated with sleep regulation. In contrast, the GABAergic and cholinergic pathways, which play important roles in promoting sleep, were downregulated in the bmal1a-mut-overexpressing zebrafish. Concordantly, sleep time of zebrafish overexpressing clocka-mut and bmal1a-mut were significantly less than the zebrafish overexpressing the wild-type genes, respectively. These findings support our hypothesis that canonical circadian clock genes may have evolved adaptively to enhance circadian regulation ability relating to sleep in cetaceans and, in turn, contribute to the formation of USWS.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 3","pages":"e1011598"},"PeriodicalIF":4.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11919277/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659445","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":"MEOX1-mediated transcriptional regulation of circABHD3 exacerbates hepatic fibrosis through promoting m6A/YTHDF2-dependent YPEL3 mRNA decay to activate β-catenin signaling.","authors":"Limin Chen, Hui Yang, Juan Wang, Haoye Zhang, Kangkang Fu, Yu Yan, Zhenguo Liu","doi":"10.1371/journal.pgen.1011622","DOIUrl":"10.1371/journal.pgen.1011622","url":null,"abstract":"<p><strong>Background: </strong>Hepatic fibrosis may progress to liver cirrhosis and eventually cause death. Epithelial-mesenchymal transition (EMT) of hepatocytes plays critical roles in hepatic fibrosis. Exploring the mechanisms underlying EMT is crucial for a better understanding of hepatic fibrosis pathogenesis.</p><p><strong>Methods: </strong>Hepatocyte EMT wad induced with TGF-β1 and evaluated by Western blotting and immunofluorescence staining. Methylated RNA immunoprecipitation (MeRIP) was applied to assess N6-methyladenosine (m6A) modification. RIP and RNA pull-down assays were performed to analyze the interaction between circABHD3, YTHDF2 and YPEL3 mRNA. MEOX1-mediated transcription of ABHD3 was examined by luciferase and chromatin immunoprecipitation (ChIP). Mice were intraperitoneally injected with CCl4 or treated with bile duct ligation (BDL) surgery for hepatic fibrosis induction. Liver injury and collagen deposition were examined with hematoxylin and eosin (HE), Masson, and Sirius Red staining. Alanine transaminase (ALT), aspartate transaminase (AST) and hydroxyproline (HYP) were examined using ELISA.</p><p><strong>Results: </strong>CircABHD3 was upregulated in in vitro and in vivo models of hepatic fibrosis and patients. Knockdown of circABHD3 inhibited TGF-β1-induced expression of fibrosis markers, EMT and mitochondrial impairment in hepatocytes. MEOX1 could directly bind to the promoter of ABHD3 to facilitate its transcription and subsequent circABHD3 generation. Knockdown of MEOX1 suppressed TGF-β1-induced EMT and mitochondrial impairment through suppression of circABHD3. CircABHD3 destabilized YPEL3 mRNA via promoting YTHDF2-dependent recognition of m6A-modified YPEL3 mRNA to trigger β-catenin signaling activation. Furthermore, circABHD3 silencing-mediated inhibition of EMT and mitochondrial impairment was counteracted by YPEL3 knockdown and activation of β-catenin signaling. Depletion of circABHD3 significantly reduced EMT, mitochondrial impairment and hepatic fibrosis via promoting YPEL3 expression and suppressing β-catenin signaling in vivo.</p><p><strong>Conclusion: </strong>MEOX1-mediated generation of circABHD3 promotes EMT and mitochondrial impairment by enhancing YTHDF2-mediated degradation of YPEL3 mRNA and activating downstream β-catenin signaling, thus exacerbating hepatic fibrosis.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 3","pages":"e1011622"},"PeriodicalIF":4.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11918346/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659468","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":"Roles of P-body factors in Candida albicans filamentation and stress response.","authors":"Melissa A Tosiano, Frederick Lanni, Aaron P Mitchell, C Joel McManus","doi":"10.1371/journal.pgen.1011632","DOIUrl":"10.1371/journal.pgen.1011632","url":null,"abstract":"<p><p>Hyphal growth is strongly associated with virulence in the human fungal pathogen Candida albicans. While hyphal transcriptional networks have been the subject of intense study, relatively little is known about post-transcriptional regulation. Previous work reported that P-Body (PB) factors Dhh1 and Edc3 were required for C. albicans virulence and filamentation, suggesting an essential role for post-transcriptional regulation of these processes. However, the molecular roles of these factors have not been determined. To further study the function of PB factors in filamentation, we generated homozygous deletions of DHH1 and EDC3 in diverse prototrophic clinical strains using transient CRISPR-Cas9. Homozygous DHH1 deletion strongly impaired growth, altered filamentation, and exhibited unusual colony morphology in response to heat stress in five strain backgrounds. Using RNA-seq, we found DHH1 deletion disrupts the regulation of thousands of genes under both yeast and hyphal growth conditions in SC5314 and P57055. This included upregulation of many stress response genes in the absence of external stress, similar to deletion of the S. cerevisiae DHH1 homolog. In contrast, we found EDC3 was not required for heat tolerance or filamentation in diverse strains. These results support a model in which DHH1, but not EDC3, represses hyphal stress response transcripts in yeast and remodels the transcriptome during filamentation. Our work supports distinct requirements for specific mRNA decay factors, bolstering evidence for post-transcriptional regulation of filamentation in C. albicans.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 3","pages":"e1011632"},"PeriodicalIF":4.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143651545","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":"TRIM21 modulates stability of pro-survival non-coding RNA vtRNA1-1 in human hepatocellular carcinoma cells.","authors":"EunBin Kong, Norbert Polacek","doi":"10.1371/journal.pgen.1011614","DOIUrl":"10.1371/journal.pgen.1011614","url":null,"abstract":"<p><p>Recent studies expanded our knowledge of diverse pro-survival functions of short non-coding vault RNAs. One of the human vault RNA paralogs, vtRNA1-1, modulates several intracellular processes, including proliferation, apoptosis, autophagy, and drug resistance in various types of human cancer cells. However, protein interaction partners and mechanisms by which vtRNA1-1 levels are controlled within the cells remained elusive. Here, we describe a regulatory process for vtRNA1-1 stabilization mediated by the newly identified interacting proteins, TRIM21 and TRIM25, in human hepatocellular carcinoma (HCC) cells. Depleting TRIM21 or TRIM25 reduced the stability of vtRNA1-1 both in vivo and in vitro. We also identified the responsible sequence of vtRNA1-1 for the stability regulation by TRIM21 and TRIM25 and revealed another critical factor for vtRNA1-1 stability, an NSUN2-mediated methylation at C69 of vtRNA1-1. Consequently, our findings demonstrated that the TRIM proteins govern the stability of vtRNA1-1 depending on its methylation status in HCC cells. Since vtRNA1-1 is crucial for pro-survival characteristics in HCC cells, insight into vtRNA1-1 protein binding partners and the regulation of its stability can impact the development of new anticancer strategies.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 3","pages":"e1011614"},"PeriodicalIF":4.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11940608/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143651599","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":"Local genetic covariance analysis with lipid traits identifies novel loci for early-onset Alzheimer's Disease.","authors":"Nicholas R Ray, Joseph Bradley, Elanur Yilmaz, Caghan Kizil, Jiji T Kurup, Eden R Martin, Hans-Ulrich Klein, Brian W Kunkle, David A Bennett, Philip L De Jager, Gary W Beecham, Carlos Cruchaga, Christiane Reitz","doi":"10.1371/journal.pgen.1011631","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011631","url":null,"abstract":"<p><p>The genetic component of early-onset Alzheimer disease (EOAD), accounting for ~10% of all Alzheimer's disease (AD) cases, is largely unexplained. Recent studies suggest that EOAD may be enriched for variants acting in the lipid pathway. The current study examines the shared genetic heritability between EOAD and the lipid pathway using genome-wide multi-trait genetic covariance analyses. Summary statistics were obtained from the GWAS meta-analyses of EOAD by the Alzheimer's Disease Genetics Consortium (n=19,668) and five blood lipid traits by the Global Lipids Genetics Consortium (n=1,320,016). The significant results were compared between the EOAD and lipids GWAS and genetic covariance analyses were performed via SUPERGNOVA. Genes in linkage disequilibrium (LD) with top EOAD hits in identified regions of covariance with lipid traits were scored and ranked for causality by combining evidence from gene-based analysis, AD-risk scores incorporating transcriptomic and proteomic evidence, eQTL data, eQTL colocalization analyses, DNA methylation data, and single-cell RNA sequencing analyses. Direct comparison of GWAS results showed 5 loci overlapping between EOAD and at least one lipid trait harboring APOE, TREM2, MS4A4E, LILRA5, and LRRC25. Local genetic covariance analyses identified 3 regions of covariance between EOAD and at least one lipid trait. Gene prioritization nominated 3 likely causative genes at these loci: ANKDD1B, CUZD1, and MS4A64.The current study identified genetic covariance between EOAD and lipids, providing further evidence of shared genetic architecture and mechanistic pathways between the two traits.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 3","pages":"e1011631"},"PeriodicalIF":4.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143651538","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":"map3k1 suppresses terminal differentiation of migratory eye progenitors in planarian regeneration.","authors":"Katherine C Lo, Christian P Petersen","doi":"10.1371/journal.pgen.1011457","DOIUrl":"10.1371/journal.pgen.1011457","url":null,"abstract":"<p><p>Proper stem cell targeting and differentiation is necessary for regeneration to succeed. In organisms capable of whole body regeneration, considerable progress has been made identifying wound signals initiating this process, but the mechanisms that control the differentiation of progenitors into mature organs are not fully understood. Using the planarian as a model system, we identify a novel function for map3k1, a MAP3K family member possessing both kinase and ubiquitin ligase domains, to negatively regulate terminal differentiation of stem cells during eye regeneration. Inhibition of map3k1 caused the formation of multiple ectopic eyes within the head, but without controlling overall head, brain, or body patterning. By contrast, other known regulators of planarian eye patterning like wnt11-6/wntA and notum also regulate head regionalization, suggesting map3k1 acts distinctly. Consistent with these results, eye resection and regeneration experiments suggest that unlike Wnt signaling perturbation, map3k1 inhibition did not shift the target destination of eye formation in the animal. map3k1(RNAi) ectopic eyes emerged in the regions normally occupied by migratory eye progenitors, and these animals produced a net excess of differentiated eye cells. Furthermore, the formation of ectopic eyes after map3k1 inhibition coincided with an increase to numbers of differentiated eye cells, a decrease in numbers of ovo+ eye progenitors, and also was preceded by eye progenitors prematurely expressing opsin/tyosinase markers of eye cell terminal differentiation. Therefore, map3k1 negatively regulates the process of terminal differentiation within the eye lineage. Similar ectopic eye phenotypes were also observed after inhibition of map2k4, map2k7, jnk, and p38, identifying a putative pathway through which map3k1 prevents differentiation. Together, these results suggest that map3k1 regulates a novel control point in the eye regeneration pathway which suppresses the terminal differentiation of progenitors during their migration to target destinations.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 3","pages":"e1011457"},"PeriodicalIF":4.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143651542","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":"Critical functions and key interactions mediated by the RNase E scaffolding domain in Pseudomonas aeruginosa.","authors":"Sandra Amandine Marie Geslain, Stéphane Hausmann, Johan Geiser, George Edward Allen, Diego Gonzalez, Martina Valentini","doi":"10.1371/journal.pgen.1011618","DOIUrl":"10.1371/journal.pgen.1011618","url":null,"abstract":"<p><p>The RNA degradosome is a bacterial multi-protein complex mediating mRNA processing and degradation. In Pseudomonadota, this complex assembles on the C-terminal domain (CTD) of RNase E through short linear motifs (SLiMs) that determine its composition and functionality. In the human pathogen Pseudomonas aeruginosa, the RNase E CTD exhibits limited similarity to that of model organisms, impeding our understanding of RNA metabolic processes in this bacterium. Our study systematically maps the interactions mediated by the P. aeruginosa RNase E CTD and highlights its critical role in transcript regulation and cellular functions. We identified the SLiMs crucial for membrane attachment, RNA binding and complex clustering, as well as for direct binding to the core components PNPase and RhlB. Transcriptome analyses of RNase E CTD mutants revealed altered expression of genes involved in quorum sensing, type III secretion, and amino acid metabolism. Additionally, we show that the mutants are impaired in cold adaptation, pH response, and virulence in an infection model. Overall, this work establishes the essential role of the RNA degradosome in driving bacterial adaptability and pathogenicity.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 3","pages":"e1011618"},"PeriodicalIF":4.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143651585","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":"The USH3A causative gene clarin1 functions in Müller glia to maintain retinal photoreceptors.","authors":"Hannah J T Nonarath, Samantha L Simpson, Tricia L Slobodianuk, Hai Tran, Ross F Collery, Astra Dinculescu, Brian A Link","doi":"10.1371/journal.pgen.1011205","DOIUrl":"10.1371/journal.pgen.1011205","url":null,"abstract":"<p><p>Mutations in CLRN1 cause Usher syndrome type IIIA (USH3A), an autosomal recessive disorder characterized by hearing and vision loss, and often accompanied by vestibular dysfunction. The identity of the cell types responsible for the pathology and mechanisms leading to vision loss in USH3A remains elusive. To address this, we employed CRISPR/Cas9 technology to delete a large region in the coding and untranslated (UTR) region of zebrafish clrn1. The retinas of clrn1 mutant larvae exhibited sensitivity to cell stress, along with age-dependent loss of function and degeneration in the photoreceptor layer. Investigation revealed disorganization in the outer retina in clrn1 mutants, including actin-based structures of the Müller glia and photoreceptor cells. To assess cell-specific contributions to USH3A pathology, we specifically re-expressed clrn1 in either Müller glia or photoreceptor cells. Müller glia re-expression of clrn1 prevented the elevated cell death observed in larval clrn1 mutant zebrafish exposed to high-intensity light. Notably, the degree of phenotypic rescue correlated with the level of Clrn1 re-expression. Surprisingly, high levels of Clrn1 expression enhanced cell death in both wild-type and clrn1 mutant animals. However, rod- or cone-specific Clrn1 re-expression did not reduce the extent of cell death. Taken together, our findings underscore three crucial insights. First, clrn1 mutant zebrafish exhibit key pathological features of USH3A; second, Clrn1 within Müller glia plays a pivotal role in photoreceptor maintenance, with its expression requiring controlled regulation; third, the reliance of photoreceptors on Müller glia suggests a structural support mechanism, possibly through direct interactions between Müller glia and photoreceptors mediated in part by Clrn1 protein.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 3","pages":"e1011205"},"PeriodicalIF":4.0,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11925288/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143606428","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":"Haplotype-based analysis distinguishes maternal-fetal genetic contribution to pregnancy-related outcomes.","authors":"Amit K Srivastava, Julius Juodakis, Pol Sole-Navais, Jing Chen, Jonas Bacelis, Kari Teramo, Mikko Hallman, Pal R Njølstad, David M Evans, Bo Jacobsson, Louis J Muglia, Ge Zhang","doi":"10.1371/journal.pgen.1011575","DOIUrl":"10.1371/journal.pgen.1011575","url":null,"abstract":"<p><p>Genotype-based approaches for the estimation of SNP-based narrow-sense heritability ([Formula: see text]) have limited utility in pregnancy-related outcomes due to confounding by the shared alleles between mother and child. Here, we propose a haplotype-based approach to estimate the genetic variance attributable to three haplotypes - maternal transmitted ([Formula: see text]), maternal non-transmitted ([Formula: see text]) and paternal transmitted ([Formula: see text]) in mother-child pairs. We show through extensive simulations that our haplotype-based approach outperforms the conventional and contemporary approaches for resolving the contribution of maternal and fetal effects, particularly when m1 and p1 have different effects in the offspring. We apply this approach to estimate the explicit and relative maternal-fetal genetic contribution to the phenotypic variance of gestational duration and gestational duration-adjusted fetal size measurements at birth in 10,375 mother-child pairs. The results reveal that variance of gestational duration is mainly attributable to m1 and m2 ([Formula: see text]). In contrast, variance of fetal size measurements at birth are mainly attributable to m1 and p1 ([Formula: see text]). Our results suggest that gestational duration and fetal size measurements are primarily genetically determined by the maternal and fetal genomes, respectively. In addition, a greater contribution of m1 as compared to m2 and p1 ([Formula: see text]) to birth length and head circumference suggests a substantial influence of correlated maternal-fetal genetic effects on these traits. Our newly developed approach provides a direct and robust alternative for resolving explicit maternal and fetal genetic contributions to the phenotypic variance of pregnancy-related outcomes.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 3","pages":"e1011575"},"PeriodicalIF":4.0,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11918446/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143597927","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":"Fission yeast Caprin protein is required for efficient heterochromatin establishment.","authors":"Haidao Zhang, Ekaterina Kapitonova, Adriana Orrego, Christos Spanos, Joanna Strachan, Elizabeth H Bayne","doi":"10.1371/journal.pgen.1011620","DOIUrl":"10.1371/journal.pgen.1011620","url":null,"abstract":"<p><p>Heterochromatin is a key feature of eukaryotic genomes that serves important regulatory and structural roles in regions such as centromeres. In fission yeast, maintenance of existing heterochromatic domains relies on positive feedback loops involving histone methylation and non-coding RNAs. However, requirements for de novo establishment of heterochromatin are less well understood. Here, through a cross-based assay we have identified a novel factor influencing the efficiency of heterochromatin establishment. We determine that the previously uncharacterised protein is an ortholog of human Caprin1, an RNA-binding protein linked to stress granule formation. We confirm that the fission yeast ortholog, here named Cpn1, also associates with stress granules, and we uncover evidence of interplay between heterochromatin integrity and ribonucleoprotein (RNP) granule formation, with heterochromatin mutants showing reduced granule formation in the presence of stress, but increased granule formation in the absence of stress. We link this to regulation of non-coding heterochromatic transcripts, since in heterochromatin-deficient cells, Cpn1 can be seen to colocalise with accumulating pericentromeric transcripts, and absence of Cpn1 leads to hyperaccumulation of these RNAs at centromeres. Together, our findings unveil a novel link between RNP homeostasis and heterochromatin assembly, and implicate Cpn1 and associated factors in facilitating efficient heterochromatin establishment by enabling removal of excess transcripts that would otherwise impair assembly processes.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 3","pages":"e1011620"},"PeriodicalIF":4.0,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11918387/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143597926","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}