PLoS Genetics最新文献_第2页

A comprehensive framework for trans-ancestry pathway analysis using GWAS summary data from diverse populations. 利用来自不同人群的 GWAS 摘要数据进行跨祖先通路分析的综合框架。

IF 4 2区生物学

PLoS Genetics Pub Date : 2024-10-23 eCollection Date: 2024-10-01 DOI: 10.1371/journal.pgen.1011322

Sheng Fu, William Wheeler, Xiaoyu Wang, Xing Hua, Devika Godbole, Jubao Duan, Bin Zhu, Lu Deng, Fei Qin, Haoyu Zhang, Jianxin Shi, Kai Yu

{"title":"A comprehensive framework for trans-ancestry pathway analysis using GWAS summary data from diverse populations.","authors":"Sheng Fu, William Wheeler, Xiaoyu Wang, Xing Hua, Devika Godbole, Jubao Duan, Bin Zhu, Lu Deng, Fei Qin, Haoyu Zhang, Jianxin Shi, Kai Yu","doi":"10.1371/journal.pgen.1011322","DOIUrl":"10.1371/journal.pgen.1011322","url":null,"abstract":"As more multi-ancestry GWAS summary data become available, we have developed a comprehensive trans-ancestry pathway analysis framework that effectively utilizes this diverse genetic information. Within this framework, we evaluated various strategies for integrating genetic data at different levels-SNP, gene, and pathway-from multiple ancestry groups. Through extensive simulation studies, we have identified robust strategies that demonstrate superior performance across diverse scenarios. Applying these methods, we analyzed 6,970 pathways for their association with schizophrenia, incorporating data from African, East Asian, and European populations. Our analysis identified over 200 pathways significantly associated with schizophrenia, even after excluding genes near genome-wide significant loci. This approach substantially enhances detection efficiency compared to traditional single-ancestry pathway analysis and the conventional approach that amalgamates single-ancestry pathway analysis results across different ancestry groups. Our framework provides a flexible and effective tool for leveraging the expanding pool of multi-ancestry GWAS summary data, thereby improving our ability to identify biologically relevant pathways that contribute to disease susceptibility.","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11534268/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142511169","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}

引用次数: 0

Trajectory-centric framework TrajAtlas reveals multi-scale differentiation heterogeneity among cells, genes, and gene modules in osteogenesis. 以轨迹为中心的框架 TrajAtlas 揭示了成骨过程中细胞、基因和基因模块之间的多尺度分化异质性。

IF 4 2区生物学

PLoS Genetics Pub Date : 2024-10-22 eCollection Date: 2024-10-01 DOI: 10.1371/journal.pgen.1011319

Litian Han, Yaoting Ji, Yiqian Yu, Yueqi Ni, Hao Zeng, Xiaoxin Zhang, Huan Liu, Yufeng Zhang

{"title":"Trajectory-centric framework TrajAtlas reveals multi-scale differentiation heterogeneity among cells, genes, and gene modules in osteogenesis.","authors":"Litian Han, Yaoting Ji, Yiqian Yu, Yueqi Ni, Hao Zeng, Xiaoxin Zhang, Huan Liu, Yufeng Zhang","doi":"10.1371/journal.pgen.1011319","DOIUrl":"10.1371/journal.pgen.1011319","url":null,"abstract":"Osteoblasts, the key cells responsible for bone formation and the maintenance of skeletal integrity, originate from a diverse array of progenitor cells. However, the mechanisms underlying osteoblast differentiation from these multiple osteoprogenitors remain poorly understood. To address this knowledge gap, we developed a comprehensive framework to investigate osteoblast differentiation at multiple scales, encompassing cells, genes, and gene modules. We constructed a reference atlas focused on differentiation, which incorporates various osteoprogenitors and provides a seven-level cellular taxonomy. To reconstruct the differentiation process, we developed a model that identifies the transcription factors and pathways involved in differentiation from different osteoprogenitors. Acknowledging that covariates such as age and tissue type can influence differentiation, we created an algorithm to detect differentially expressed genes throughout the differentiation process. Additionally, we implemented methods to identify conserved pseudotemporal gene modules across multiple samples. Overall, our framework systematically addresses the heterogeneity observed during osteoblast differentiation from diverse sources, offering novel insights into the complexities of bone formation and serving as a valuable resource for understanding osteogenesis.","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11530032/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142511174","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}

引用次数: 0

The Drosophila circadian clock gene cycle controls the development of clock neurons. 果蝇的昼夜节律时钟基因周期控制着时钟神经元的发育。

IF 4 2区生物学

PLoS Genetics Pub Date : 2024-10-21 eCollection Date: 2024-10-01 DOI: 10.1371/journal.pgen.1011441

Grace Biondi, Gina McCormick, Maria P Fernandez

{"title":"The Drosophila circadian clock gene cycle controls the development of clock neurons.","authors":"Grace Biondi, Gina McCormick, Maria P Fernandez","doi":"10.1371/journal.pgen.1011441","DOIUrl":"10.1371/journal.pgen.1011441","url":null,"abstract":"Daily behavioral and physiological rhythms are controlled by the brain's circadian timekeeping system, a synchronized network of neurons that maintains endogenous molecular oscillations. These oscillations are based on transcriptional feedback loops of clock genes, which in Drosophila include the transcriptional activators Clock (Clk) and cycle (cyc). While the mechanisms underlying this molecular clock are very well characterized, the roles that the core clock genes play in neuronal physiology and development are much less understood. The Drosophila timekeeping center is composed of ~150 clock neurons, among which the four small ventral lateral neurons (sLNvs) are the most dominant pacemakers under constant conditions. Here, we show that downregulating the clock gene cyc specifically in the Pdf-expressing neurons leads to decreased fasciculation both in larval and adult brains. This effect is due to a developmental role of cyc, as both knocking down cyc or expressing a dominant negative form of cyc exclusively during development lead to defasciculation phenotypes in adult clock neurons. Clk downregulation also leads to developmental effects on sLNv morphology. Our results reveal a non-circadian role for cyc, shedding light on the additional functions of circadian clock genes in the development of the nervous system.","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11527286/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478553","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}

引用次数: 0

HTL/KAI2 signaling substitutes for light to control plant germination. HTL/KAI2 信号可替代光来控制植物萌芽。

IF 4 2区生物学

PLoS Genetics Pub Date : 2024-10-21 eCollection Date: 2024-10-01 DOI: 10.1371/journal.pgen.1011447

Jenna E Hountalas, Michael Bunsick, Zhenhua Xu, Andrea A Taylor, Gianni Pescetto, George Ly, François-Didier Boyer, Christopher S P McErlean, Shelley Lumba

{"title":"HTL/KAI2 signaling substitutes for light to control plant germination.","authors":"Jenna E Hountalas, Michael Bunsick, Zhenhua Xu, Andrea A Taylor, Gianni Pescetto, George Ly, François-Didier Boyer, Christopher S P McErlean, Shelley Lumba","doi":"10.1371/journal.pgen.1011447","DOIUrl":"10.1371/journal.pgen.1011447","url":null,"abstract":"Plants monitor multiple environmental cues, such as light and temperature, to ensure they germinate at the right time and place. Some specialist plants, like ephemeral fire-following weeds and root parasitic plants, germinate primarily in response to small molecules found in specific environments. Although these species come from distinct clades, they use the same HYPOSENSITIVE TO LIGHT/KARRIKIN INSENSITIVE 2 (HTL/KAI2) signaling pathway, to perceive different small molecules suggesting convergent evolution on this pathway. Here, we show that HTL/KAI2 signaling in Arabidopsis thaliana bypasses the light requirement for germination. The HTL/KAI2 downstream component, SUPPRESSOR OF MAX2 1 (SMAX1) accumulates in the dark and is necessary for PHYTOCHROME INTERACTING FACTOR 1/PHYTOCHROME INTERACTING FACTOR 3-LIKE 5 (PIF1/PIL5) to regulate hormone response pathways conducive to germination. The interaction of HTL/KAI2 and light signaling may help to explain how specialist plants like ephemeral and parasitic weeds evolved their germination behaviour in response to specific environments.","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11527322/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478538","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}

引用次数: 0

LD-transpeptidation is crucial for fitness and polar growth in Agrobacterium tumefaciens. LD-transpeptidation 对农杆菌的适应性和极性生长至关重要。

IF 4 2区生物学

PLoS Genetics Pub Date : 2024-10-21 eCollection Date: 2024-10-01 DOI: 10.1371/journal.pgen.1011449

Alena Aliashkevich, Thomas Guest, Laura Alvarez, Michael C Gilmore, Daniel Rea, Jennifer Amstutz, André Mateus, Bastian Schiffthaler, Iñigo Ruiz, Athanasios Typas, Mikhail M Savitski, Pamela J B Brown, Felipe Cava

{"title":"LD-transpeptidation is crucial for fitness and polar growth in Agrobacterium tumefaciens.","authors":"Alena Aliashkevich, Thomas Guest, Laura Alvarez, Michael C Gilmore, Daniel Rea, Jennifer Amstutz, André Mateus, Bastian Schiffthaler, Iñigo Ruiz, Athanasios Typas, Mikhail M Savitski, Pamela J B Brown, Felipe Cava","doi":"10.1371/journal.pgen.1011449","DOIUrl":"10.1371/journal.pgen.1011449","url":null,"abstract":"Peptidoglycan (PG), a mesh-like structure which is the primary component of the bacterial cell wall, is crucial to maintain cell integrity and shape. While most bacteria rely on penicillin binding proteins (PBPs) for crosslinking, some species also employ LD-transpeptidases (LDTs). Unlike PBPs, the essentiality and biological functions of LDTs remain largely unclear. The Hyphomicrobiales order of the Alphaproteobacteria, known for their polar growth, have PG which is unusually rich in LD-crosslinks, suggesting that LDTs may play a more significant role in PG synthesis in these bacteria. Here, we investigated LDTs in the plant pathogen Agrobacterium tumefaciens and found that LD-transpeptidation, resulting from at least one of 14 putative LDTs present in this bacterium, is essential for its survival. Notably, a mutant lacking a distinctive group of 7 LDTs which are broadly conserved among the Hyphomicrobiales exhibited reduced LD-crosslinking and tethering of PG to outer membrane β-barrel proteins. Consequently, this mutant suffered severe fitness loss and cell shape rounding, underscoring the critical role played by these Hyphomicrobiales-specific LDTs in maintaining cell wall integrity and promoting elongation. Tn-sequencing screens further revealed non-redundant functions for A. tumefaciens LDTs. Specifically, Hyphomicrobiales-specific LDTs exhibited synthetic genetic interactions with division and cell cycle proteins, and a single LDT from another group. Additionally, our findings demonstrate that strains lacking all LDTs except one displayed distinctive phenotypic profiles and genetic interactions. Collectively, our work emphasizes the critical role of LD-crosslinking in A. tumefaciens cell wall integrity and growth and provides insights into the functional specialization of these crosslinking activities.","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11527210/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478549","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}

引用次数: 0

Celsr3 drives development and connectivity of the acoustic startle hindbrain circuit. Celsr3驱动声惊跳后脑回路的发育和连接

IF 4 2区生物学

PLoS Genetics Pub Date : 2024-10-21 eCollection Date: 2024-10-01 DOI: 10.1371/journal.pgen.1011415

Joy H Meserve, Maria F Navarro, Elelbin A Ortiz, Michael Granato

{"title":"Celsr3 drives development and connectivity of the acoustic startle hindbrain circuit.","authors":"Joy H Meserve, Maria F Navarro, Elelbin A Ortiz, Michael Granato","doi":"10.1371/journal.pgen.1011415","DOIUrl":"10.1371/journal.pgen.1011415","url":null,"abstract":"In the developing brain, groups of neurons organize into functional circuits that direct diverse behaviors. One such behavior is the evolutionarily conserved acoustic startle response, which in zebrafish is mediated by a well-defined hindbrain circuit. While numerous molecular pathways that guide neurons to their synaptic partners have been identified, it is unclear if and to what extent distinct neuron populations in the startle circuit utilize shared molecular pathways to ensure coordinated development. Here, we show that the planar cell polarity (PCP)-associated atypical cadherins Celsr3 and Celsr2, as well as the Celsr binding partner Frizzled 3a/Fzd3a, are critical for axon guidance of two neuron types that form synapses with each other: the command-like neuron Mauthner cells that drive the acoustic startle escape response, and spiral fiber neurons which provide excitatory input to Mauthner cells. We find that Mauthner axon growth towards synaptic targets is vital for Mauthner survival. We also demonstrate that symmetric spiral fiber input to Mauthner cells is critical for escape direction, which is necessary to respond to directional threats. Moreover, we identify distinct roles for Celsr3 and Celsr2, as Celsr3 is required for startle circuit development while Celsr2 is dispensable, though Celsr2 can partially compensate for loss of Celsr3 in Mauthner cells. This contrasts with facial branchiomotor neuron migration in the hindbrain, which requires Celsr2 while we find that Celsr3 is dispensable. Combined, our data uncover critical and distinct roles for individual PCP components during assembly of the acoustic startle hindbrain circuit.","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11527297/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478537","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}

引用次数: 0

Candida albicans pathways that protect against organic peroxides and lipid peroxidation. 白色念珠菌保护有机过氧化物和脂质过氧化的途径。

IF 4 2区生物学

PLoS Genetics Pub Date : 2024-10-21 eCollection Date: 2024-10-01 DOI: 10.1371/journal.pgen.1011455

Kara A Swenson, Kyunghun Min, James B Konopka

{"title":"Candida albicans pathways that protect against organic peroxides and lipid peroxidation.","authors":"Kara A Swenson, Kyunghun Min, James B Konopka","doi":"10.1371/journal.pgen.1011455","DOIUrl":"10.1371/journal.pgen.1011455","url":null,"abstract":"Human fungal pathogens must survive diverse reactive oxygen species (ROS) produced by host immune cells that can oxidize a range of cellular molecules including proteins, lipids, and DNA. Formation of lipid radicals can be especially damaging, as it leads to a chain reaction of lipid peroxidation that causes widespread damage to the plasma membrane. Most previous studies on antioxidant pathways in fungal pathogens have been conducted with hydrogen peroxide, so the pathways used to combat organic peroxides and lipid peroxidation are not well understood. The most well-known peroxidase in Candida albicans, catalase, can only act on hydrogen peroxide. We therefore characterized a family of four glutathione peroxidases (GPxs) that were predicted to play an important role in reducing organic peroxides. One of the GPxs, Gpx3 is also known to activate the Cap1 transcription factor that plays the major role in inducing antioxidant genes in response to ROS. Surprisingly, we found that the only measurable role of the GPxs is activation of Cap1 and did not find a significant role for GPxs in the direct detoxification of peroxides. Furthermore, a CAP1 deletion mutant strain was highly sensitive to organic peroxides and oxidized lipids, indicating an important role for antioxidant genes upregulated by Cap1 in protecting cells from organic peroxides. We identified GLR1 (Glutathione reductase), a gene upregulated by Cap1, as important for protecting cells from oxidized lipids, implicating glutathione utilizing enzymes in the protection against lipid peroxidation. Furthermore, an RNA-sequencing study in C. albicans showed upregulation of a diverse set of antioxidant genes and protein damage pathways in response to organic peroxides. Overall, our results identify novel mechanisms by which C. albicans responds to oxidative stress resistance which open new avenues for understanding how fungal pathogens resist ROS in the host.","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11527291/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478536","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}

引用次数: 0

MBL-1/Muscleblind regulates neuronal differentiation and controls the splicing of a terminal selector in Caenorhabditis elegans. MBL-1/Muscleblind调控秀丽隐杆线虫的神经元分化并控制末端选择器的剪接。

IF 4 2区生物学

PLoS Genetics Pub Date : 2024-10-18 eCollection Date: 2024-10-01 DOI: 10.1371/journal.pgen.1011276

Ho Ming Terence Lee, Hui Yuan Lim, Haoming He, Chun Yin Lau, Chaogu Zheng

{"title":"MBL-1/Muscleblind regulates neuronal differentiation and controls the splicing of a terminal selector in Caenorhabditis elegans.","authors":"Ho Ming Terence Lee, Hui Yuan Lim, Haoming He, Chun Yin Lau, Chaogu Zheng","doi":"10.1371/journal.pgen.1011276","DOIUrl":"10.1371/journal.pgen.1011276","url":null,"abstract":"The muscleblind family of mRNA splicing regulators is conserved across species and regulates the development of muscles and the nervous system. However, how Muscleblind proteins regulate neuronal fate specification and neurite morphogenesis at the single-neuron level is not well understood. In this study, we found that the C. elegans Muscleblind/MBL-1 promotes axonal growth in the touch receptor neurons (TRNs) by regulating microtubule stability and polarity. Transcriptomic analysis identified dozens of MBL-1-controlled splicing events in genes related to neuronal differentiation or microtubule functions. Among the MBL-1 targets, the LIM-domain transcription factor mec-3 is the terminal selector for the TRN fate and induces the expression of many TRN terminal differentiation genes. MBL-1 promotes the splicing of the mec-3 long isoform, which is essential for TRN fate specification, and inhibits the short isoforms that have much weaker activities in activating downstream genes. MBL-1 promotes mec-3 splicing through three \"YGCU(U/G)Y\" motifs located in or downstream of the included exon, which is similar to the mechanisms used by mammalian Muscleblind and suggests a deeply conserved context-dependency of the splicing regulation. Interestingly, the expression of mbl-1 in the TRNs is dependent on the mec-3 long isoform, indicating a positive feedback loop between the splicing regulator and the terminal selector. Finally, through a forward genetic screen, we found that MBL-1 promotes neurite growth partly by inhibiting the DLK-1/p38 MAPK pathway. In summary, our study provides mechanistic understanding of the role of Muscleblind in regulating cell fate specification and neuronal morphogenesis.","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11524483/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478551","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}

引用次数: 0

Behavioral screening reveals a conserved residue in Y-Box RNA-binding protein required for associative learning and memory in C. elegans. 行为筛选揭示了Y-Box RNA结合蛋白中的一个保守残基，该残基是优雅鼠联想学习和记忆所必需的。

IF 4 2区生物学

PLoS Genetics Pub Date : 2024-10-18 eCollection Date: 2024-10-01 DOI: 10.1371/journal.pgen.1011443

Ashley N Hayden, Katie L Brandel, Edward W Pietryk, Paul R Merlau, Priyadharshini Vijayakumar, Emily J Leptich, Elizabeth S Gaytan, Meredith I Williams, Connie W Ni, Hsiao-Tuan Chao, Jill A Rosenfeld, Rachel N Arey

{"title":"Behavioral screening reveals a conserved residue in Y-Box RNA-binding protein required for associative learning and memory in C. elegans.","authors":"Ashley N Hayden, Katie L Brandel, Edward W Pietryk, Paul R Merlau, Priyadharshini Vijayakumar, Emily J Leptich, Elizabeth S Gaytan, Meredith I Williams, Connie W Ni, Hsiao-Tuan Chao, Jill A Rosenfeld, Rachel N Arey","doi":"10.1371/journal.pgen.1011443","DOIUrl":"10.1371/journal.pgen.1011443","url":null,"abstract":"RNA-binding proteins (RBPs) regulate translation and plasticity which are required for memory. RBP dysfunction has been linked to a range of neurological disorders where cognitive impairments are a key symptom. However, of the 2,000 RBPs in the human genome, many are uncharacterized with regards to neurological phenotypes. To address this, we used the model organism C. elegans to assess the role of 20 conserved RBPs in memory. We identified eight previously uncharacterized memory regulators, three of which are in the C. elegans Y-Box (CEY) RBP family. Of these, we determined that cey-1 is the closest ortholog to the mammalian Y-Box (YBX) RBPs. We found that CEY-1 is both necessary in the nervous system for memory ability and sufficient to promote memory. Leveraging human datasets, we found both copy number variation losses and single nucleotide variants in YBX1 and YBX3 in individuals with neurological symptoms. We identified one predicted deleterious YBX3 variant of unknown significance, p.Asn127Tyr, in two individuals with neurological symptoms. Introducing this variant into endogenous cey-1 locus caused memory deficits in the worm. We further generated two humanized worm lines expressing human YBX3 or YBX1 at the cey-1 locus to test evolutionary conservation of YBXs in memory and the potential functional significance of the p.Asn127Tyr variant. Both YBX1/3 can functionally replace cey-1, and introduction of p.Asn127Tyr into the humanized YBX3 locus caused memory deficits. Our study highlights the worm as a model to reveal memory regulators and identifies YBX dysfunction as a potential new source of rare neurological disease.","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11524487/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478535","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}

引用次数: 0

Proximity labeling reveals new functional relationships between meiotic recombination proteins in S. cerevisiae. 接近标记揭示了 S. cerevisiae 中减数分裂重组蛋白之间的新功能关系。

IF 4 2区生物学

PLoS Genetics Pub Date : 2024-10-15 eCollection Date: 2024-10-01 DOI: 10.1371/journal.pgen.1011432

Karen Voelkel-Meiman, Jennifer C Liddle, Jeremy L Balsbaugh, Amy J MacQueen

{"title":"Proximity labeling reveals new functional relationships between meiotic recombination proteins in S. cerevisiae.","authors":"Karen Voelkel-Meiman, Jennifer C Liddle, Jeremy L Balsbaugh, Amy J MacQueen","doi":"10.1371/journal.pgen.1011432","DOIUrl":"10.1371/journal.pgen.1011432","url":null,"abstract":"Several protein ensembles facilitate crossover recombination and the associated assembly of synaptonemal complex (SC) during meiosis. In yeast, meiosis-specific factors including the DNA helicase Mer3, the \"ZZS\" complex consisting of Zip4, Zip2, and Spo16, the RING-domain protein Zip3, and the MutSγ heterodimer collaborate with crossover-promoting activity of the SC component, Zip1, to generate crossover-designated recombination intermediates. These ensembles also promote SC formation - the organized assembly of Zip1 with other structural proteins between aligned chromosome axes. We used proximity labeling to investigate spatial relationships between meiotic recombination and SC proteins in S. cerevisiae. We find that recombination initiation and SC factors are dispensable for proximity labeling of Zip3 by ZZS components, but proteins associated with early steps in recombination are required for Zip3 proximity labeling by MutSγ, suggesting that MutSγ joins Zip3 only after a recombination intermediate has been generated. We also find that zip1 separation-of-function mutants that are crossover deficient but still assemble SC fail to generate protein ensembles where Zip3 can engage ZZS and/or MutSγ. The SC structural protein Ecm11 is proximity labeled by ZZS proteins in a Zip4-dependent and Zip1-independent manner, but labeling of Ecm11 by Zip3 and MutSγ requires, at least in part, Zip1. Finally, mass spectrometry analysis of biotinylated proteins in eleven proximity labeling strains uncovered shared proximity targets of SC and crossover-associated proteins, some of which have not previously been implicated in meiotic recombination or SC formation, highlighting the potential of proximity labeling as a discovery tool.","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11508090/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478552","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}

引用次数: 0