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Characterizing the landscape of gene expression variance in humans. 人类基因表达变异的特征。
IF 4.5 2区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2023-07-01 DOI: 10.1371/journal.pgen.1010833
Scott Wolf, Diogo Melo, Kristina M Garske, Luisa F Pallares, Amanda J Lea, Julien F Ayroles

Gene expression variance has been linked to organismal function and fitness but remains a commonly neglected aspect of molecular research. As a result, we lack a comprehensive understanding of the patterns of transcriptional variance across genes, and how this variance is linked to context-specific gene regulation and gene function. Here, we use 57 large publicly available RNA-seq data sets to investigate the landscape of gene expression variance. These studies cover a wide range of tissues and allowed us to assess if there are consistently more or less variable genes across tissues and data sets and what mechanisms drive these patterns. We show that gene expression variance is broadly similar across tissues and studies, indicating that the pattern of transcriptional variance is consistent. We use this similarity to create both global and within-tissue rankings of variation, which we use to show that function, sequence variation, and gene regulatory signatures contribute to gene expression variance. Low-variance genes are associated with fundamental cell processes and have lower levels of genetic polymorphisms, have higher gene-gene connectivity, and tend to be associated with chromatin states associated with transcription. In contrast, high-variance genes are enriched for genes involved in immune response, environmentally responsive genes, immediate early genes, and are associated with higher levels of polymorphisms. These results show that the pattern of transcriptional variance is not noise. Instead, it is a consistent gene trait that seems to be functionally constrained in human populations. Furthermore, this commonly neglected aspect of molecular phenotypic variation harbors important information to understand complex traits and disease.

基因表达变异与机体功能和适应性有关,但在分子研究中仍然是一个经常被忽视的方面。因此,我们缺乏对基因间转录变异模式的全面理解,以及这种变异如何与特定环境的基因调控和基因功能联系起来。在这里,我们使用57个大型公开可用的RNA-seq数据集来研究基因表达差异的景观。这些研究涵盖了广泛的组织,使我们能够评估跨组织和数据集是否存在一致的或多或少可变基因,以及驱动这些模式的机制。我们发现基因表达变异在不同组织和研究中大致相似,表明转录变异的模式是一致的。我们使用这种相似性来创建全局和组织内的变异排名,我们使用它来显示功能,序列变异和基因调控特征有助于基因表达变异。低变异基因与基本细胞过程相关,具有较低水平的遗传多态性,具有较高的基因-基因连通性,并且倾向于与转录相关的染色质状态相关。相比之下,高变异基因在参与免疫反应的基因、环境反应基因、即时早期基因中富集,并与较高水平的多态性相关。这些结果表明,转录变异模式不是噪声。相反,它是一种一致的基因特征,似乎在人类群体中受到功能限制。此外,这一通常被忽视的分子表型变异方面蕴藏着理解复杂性状和疾病的重要信息。
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引用次数: 0
Perturbation of protein homeostasis brings plastids at the crossroad between repair and dismantling. 蛋白质稳态的扰动使质体处于修复和拆除之间的十字路口。
IF 4.5 2区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2023-07-01 DOI: 10.1371/journal.pgen.1010344
Luca Tadini, Nicolaj Jeran, Guido Domingo, Federico Zambelli, Simona Masiero, Anna Calabritto, Elena Costantini, Sara Forlani, Milena Marsoni, Federica Briani, Candida Vannini, Paolo Pesaresi

The chloroplast proteome is a dynamic mosaic of plastid- and nuclear-encoded proteins. Plastid protein homeostasis is maintained through the balance between de novo synthesis and proteolysis. Intracellular communication pathways, including the plastid-to-nucleus signalling and the protein homeostasis machinery, made of stromal chaperones and proteases, shape chloroplast proteome based on developmental and physiological needs. However, the maintenance of fully functional chloroplasts is costly and under specific stress conditions the degradation of damaged chloroplasts is essential to the maintenance of a healthy population of photosynthesising organelles while promoting nutrient redistribution to sink tissues. In this work, we have addressed this complex regulatory chloroplast-quality-control pathway by modulating the expression of two nuclear genes encoding plastid ribosomal proteins PRPS1 and PRPL4. By transcriptomics, proteomics and transmission electron microscopy analyses, we show that the increased expression of PRPS1 gene leads to chloroplast degradation and early flowering, as an escape strategy from stress. On the contrary, the overaccumulation of PRPL4 protein is kept under control by increasing the amount of plastid chaperones and components of the unfolded protein response (cpUPR) regulatory mechanism. This study advances our understanding of molecular mechanisms underlying chloroplast retrograde communication and provides new insights into cellular responses to impaired plastid protein homeostasis.

叶绿体蛋白质组是质体和核编码蛋白质的动态镶嵌。质体蛋白稳态是通过新生合成和蛋白水解之间的平衡来维持的。细胞内的通讯途径,包括质体到细胞核的信号和蛋白质稳态机制,由基质伴侣和蛋白酶组成,根据发育和生理需要形成叶绿体蛋白质组。然而,维持完全功能的叶绿体是昂贵的,在特定的应激条件下,受损叶绿体的降解对维持健康的光合细胞器群体至关重要,同时促进营养物质重新分配到沉组织。在这项工作中,我们通过调节编码质体核糖体蛋白PRPS1和PRPL4的两个核基因的表达来解决这个复杂的调控叶绿体质量控制途径。通过转录组学、蛋白质组学和透射电镜分析,我们发现PRPS1基因的表达增加导致叶绿体降解和提早开花,作为一种逃避胁迫的策略。相反,PRPL4蛋白的过度积累是通过增加质体伴侣的数量和未折叠蛋白反应(cpUPR)调控机制的组分来控制的。这项研究促进了我们对叶绿体逆行通讯的分子机制的理解,并为细胞对质体蛋白稳态受损的反应提供了新的见解。
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引用次数: 0
The oxidative stress response, in particular the katY gene, is temperature-regulated in Yersinia pseudotuberculosis. 在假结核耶尔森菌中,氧化应激反应,特别是katY基因,是温度调节的。
IF 4.5 2区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2023-07-01 DOI: 10.1371/journal.pgen.1010669
Daniel Scheller, Franziska Becker, Andrea Wimbert, Dominik Meggers, Stephan Pienkoß, Christian Twittenhoff, Lisa R Knoke, Lars I Leichert, Franz Narberhaus
Pathogenic bacteria, such as Yersinia pseudotuberculosis encounter reactive oxygen species (ROS) as one of the first lines of defense in the mammalian host. In return, the bacteria react by mounting an oxidative stress response. Previous global RNA structure probing studies provided evidence for temperature-modulated RNA structures in the 5’-untranslated region (5’-UTR) of various oxidative stress response transcripts, suggesting that opening of these RNA thermometer (RNAT) structures at host-body temperature relieves translational repression. Here, we systematically analyzed the transcriptional and translational regulation of ROS defense genes by RNA-sequencing, qRT-PCR, translational reporter gene fusions, enzymatic RNA structure probing and toeprinting assays. Transcription of four ROS defense genes was upregulated at 37°C. The trxA gene is transcribed into two mRNA isoforms, of which the short one contains a functional RNAT. Biochemical assays validated temperature-responsive RNAT-like structures in the 5’-UTRs of sodB, sodC and katA. However, they barely conferred translational repression in Y. pseudotuberculosis at 25°C suggesting partially open structures available to the ribosome in the living cell. Upstream of katY we uncovered a novel, highly efficient RNAT that was primarily responsible for massive induction of KatY at 37°C. By phenotypic characterization of catalase mutants and through fluorometric real-time measurements of the redox-sensitive roGFP2-Orp1 reporter in these strains, we revealed KatA as the primary H2O2 scavenger. Consistent with temperature regulation of katY, we observed an improved protection of Y. pseudotuberculosis at 37°C. Our findings suggest a multilayered regulation of the oxidative stress response in Yersinia and an important role of RNAT-controlled katY expression at host body temperature. Author summary The external conditions dramatically change when a bacterial pathogen enters a mammalian host. Sensing the new situation and rapidly responding to it is of critical importance for pathogens, like Yersinia pseudotuberculosis, since they often circulate between their environmental reservoirs and a warm-blooded host. Many virulence-related genes encode a temperature-sensitive mRNA element, a so-called RNA thermometer (RNAT), in the 5’-end of their transcript. Melting of this structure at 37°C allows ribosome binding and translation initiation. The host immune system typically fights microbial pathogens by the production of reactive oxygen species (ROS). Here, we find that several ROS defense genes in Yersinia are upregulated at host body temperature to counteract the ROS attack. In particular, the massive RNAT-mediated upregulation of the catalase KatY confers protection against H2O2 at 37°C. Our study reveals a close regulatory link between temperature sensing and the oxidative stress response in a notorious food borne pathogen.
致病菌,如假结核耶尔森菌,在哺乳动物宿主中遇到活性氧(ROS)是第一道防线之一。作为回报,细菌会产生氧化应激反应。先前的全球RNA结构探测研究为各种氧化应激反应转录本的5'-非翻译区(5'-UTR)中的温度调节RNA结构提供了证据,表明在宿主体温下打开这些RNA温度计(RNAT)结构可以减轻翻译抑制。本研究通过RNA测序、qRT-PCR、翻译报告基因融合、酶促RNA结构探测和足印检测等方法,系统分析了ROS防御基因的转录和翻译调控。在37℃时,4个ROS防御基因的转录上调。trxA基因被转录成两个mRNA亚型,其中最丰富的短亚型含有一个功能性RNAT。生化分析证实了sodB、sodC和katA的5'- utr中存在温度响应的rnat样结构。然而,在25°C时,它们在假结核杆菌中几乎没有翻译抑制作用,这表明活细胞中的核糖体可以部分开放结构。在katY的翻译起始区周围,我们发现了一个新颖的、高效的RNAT,它主要负责在37°C下大量诱导katY。通过对过氧化氢酶突变体的表型表征以及对这些菌株中氧化还原敏感的roGFP2-Orp1报告基因的荧光实时测量,我们发现KatA是主要的H2O2清除剂。与katY的上调一致,我们观察到在37°C下对假结核杆菌的保护得到了改善。我们的研究结果表明,耶尔森菌的氧化应激反应存在多层调控,rnat控制的水果水果在宿主体温下的表达具有重要作用。
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引用次数: 0
PKA regulatory subunit Bcy1 couples growth, lipid metabolism, and fermentation during anaerobic xylose growth in Saccharomyces cerevisiae. PKA调控亚基Bcy1在酿酒酵母厌氧木糖生长过程中对生长、脂质代谢和发酵进行耦合。
IF 4.5 2区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2023-07-01 DOI: 10.1371/journal.pgen.1010593
Ellen R Wagner, Nicole M Nightingale, Annie Jen, Katherine A Overmyer, Mick McGee, Joshua J Coon, Audrey P Gasch

Organisms have evolved elaborate physiological pathways that regulate growth, proliferation, metabolism, and stress response. These pathways must be properly coordinated to elicit the appropriate response to an ever-changing environment. While individual pathways have been well studied in a variety of model systems, there remains much to uncover about how pathways are integrated to produce systemic changes in a cell, especially in dynamic conditions. We previously showed that deletion of Protein Kinase A (PKA) regulatory subunit BCY1 can decouple growth and metabolism in Saccharomyces cerevisiae engineered for anaerobic xylose fermentation, allowing for robust fermentation in the absence of division. This provides an opportunity to understand how PKA signaling normally coordinates these processes. Here, we integrated transcriptomic, lipidomic, and phospho-proteomic responses upon a glucose to xylose shift across a series of strains with different genetic mutations promoting either coupled or decoupled xylose-dependent growth and metabolism. Together, results suggested that defects in lipid homeostasis limit growth in the bcy1Δ strain despite robust metabolism. To further understand this mechanism, we performed adaptive laboratory evolutions to re-evolve coupled growth and metabolism in the bcy1Δ parental strain. The evolved strain harbored mutations in PKA subunit TPK1 and lipid regulator OPI1, among other genes, and evolved changes in lipid profiles and gene expression. Deletion of the evolved opi1 gene partially reverted the strain's phenotype to the bcy1Δ parent, with reduced growth and robust xylose fermentation. We suggest several models for how cells coordinate growth, metabolism, and other responses in budding yeast and how restructuring these processes enables anaerobic xylose utilization.

生物体已经进化出复杂的生理途径来调节生长、增殖、代谢和应激反应。这些途径必须得到适当的协调,以引起对不断变化的环境的适当反应。虽然在各种模型系统中已经对单个通路进行了很好的研究,但关于通路如何整合以在细胞中产生系统变化,特别是在动态条件下,仍有许多有待发现。我们之前的研究表明,蛋白激酶A (PKA)调控亚基BCY1的缺失可以使酿酒酵母的生长和代谢解耦,从而在没有分裂的情况下实现强劲的发酵。这为了解PKA信号通常如何协调这些过程提供了机会。在这里,我们整合了转录组学、脂质组学和磷酸化蛋白质组学对葡萄糖向木糖转变的反应,这些反应跨越了一系列具有不同基因突变的菌株,促进了偶联或解耦的木糖依赖性生长和代谢。总之,结果表明脂质稳态缺陷限制了bcy1Δ菌株的生长,尽管代谢强劲。为了进一步了解这一机制,我们进行了适应性实验室进化,重新进化了bcy1Δ亲本菌株的耦合生长和代谢。进化后的菌株在PKA亚基TPK1和脂质调节因子OPI1等基因中发生突变,并在脂质谱和基因表达方面发生了变化。进化的opi1基因的缺失使菌株的表型部分恢复到bcy1Δ亲本,生长减少,木糖发酵强劲。我们提出了几种细胞如何协调生长、代谢和其他反应的模型,以及如何重组这些过程使厌氧木糖利用。
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引用次数: 1
Characterization of factors that underlie transcriptional silencing in C. elegans oocytes. 秀丽隐杆线虫卵母细胞转录沉默因素的表征。
IF 4.5 2区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2023-07-01 DOI: 10.1371/journal.pgen.1010831
Mezmur D Belew, Emilie Chien, W Matthew Michael

While it has been appreciated for decades that prophase-arrested oocytes are transcriptionally silenced on a global level, the molecular pathways that promote silencing have remained elusive. Previous work in C. elegans has shown that both topoisomerase II (TOP-2) and condensin II collaborate with the H3K9me heterochromatin pathway to silence gene expression in the germline during L1 starvation, and that the PIE-1 protein silences the genome in the P-lineage of early embryos. Here, we show that all three of these silencing systems, TOP-2/condensin II, H3K9me, and PIE-1, are required for transcriptional repression in oocytes. We find that H3K9me3 marks increase dramatically on chromatin during silencing, and that silencing is under cell cycle control. We also find that PIE-1 localizes to the nucleolus just prior to silencing, and that nucleolar dissolution during silencing is dependent on TOP-2/condensin II. Our data identify both the molecular components and the trigger for genome silencing in oocytes and establish a link between PIE-1 nucleolar residency and its ability to repress transcription.

虽然几十年来人们已经认识到,前驱阻滞的卵母细胞在全球水平上是转录沉默的,但促进沉默的分子途径仍然难以捉摸。先前对秀丽隐杆线虫的研究表明,拓扑异构酶II (TOP-2)和凝聚素II与H3K9me异染色质途径协同作用,在L1饥饿期间沉默种系基因的表达,而pie1蛋白沉默了早期胚胎p谱系的基因组。在这里,我们发现所有这三种沉默系统,TOP-2/凝缩素II, H3K9me和PIE-1,都是卵母细胞转录抑制所必需的。我们发现沉默期间染色质上的H3K9me3标记显著增加,并且沉默是受细胞周期控制的。我们还发现PIE-1在沉默之前定位于核仁,而沉默期间核仁的溶解依赖于TOP-2/冷凝蛋白II。我们的数据确定了卵母细胞中基因组沉默的分子成分和触发因素,并建立了PIE-1核仁驻留与其抑制转录能力之间的联系。
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引用次数: 2
A flexible empirical Bayes approach to multivariate multiple regression, and its improved accuracy in predicting multi-tissue gene expression from genotypes. 一种灵活的经验贝叶斯方法用于多元回归,并提高了从基因型预测多组织基因表达的准确性。
IF 4.5 2区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2023-07-01 DOI: 10.1371/journal.pgen.1010539
Fabio Morgante, Peter Carbonetto, Gao Wang, Yuxin Zou, Abhishek Sarkar, Matthew Stephens

Predicting phenotypes from genotypes is a fundamental task in quantitative genetics. With technological advances, it is now possible to measure multiple phenotypes in large samples. Multiple phenotypes can share their genetic component; therefore, modeling these phenotypes jointly may improve prediction accuracy by leveraging effects that are shared across phenotypes. However, effects can be shared across phenotypes in a variety of ways, so computationally efficient statistical methods are needed that can accurately and flexibly capture patterns of effect sharing. Here, we describe new Bayesian multivariate, multiple regression methods that, by using flexible priors, are able to model and adapt to different patterns of effect sharing and specificity across phenotypes. Simulation results show that these new methods are fast and improve prediction accuracy compared with existing methods in a wide range of settings where effects are shared. Further, in settings where effects are not shared, our methods still perform competitively with state-of-the-art methods. In real data analyses of expression data in the Genotype Tissue Expression (GTEx) project, our methods improve prediction performance on average for all tissues, with the greatest gains in tissues where effects are strongly shared, and in the tissues with smaller sample sizes. While we use gene expression prediction to illustrate our methods, the methods are generally applicable to any multi-phenotype applications, including prediction of polygenic scores and breeding values. Thus, our methods have the potential to provide improvements across fields and organisms.

从基因型预测表型是数量遗传学的一项基本任务。随着技术的进步,现在可以在大样本中测量多种表型。多种表型可以共享它们的遗传成分;因此,联合建模这些表型可以通过利用在表型之间共享的效应来提高预测的准确性。然而,效应可以通过多种方式在表型之间共享,因此需要能够准确灵活地捕获效应共享模式的高效计算统计方法。在这里,我们描述了新的贝叶斯多元多元回归方法,通过使用灵活的先验,能够建模和适应不同表型的效应共享和特异性模式。仿真结果表明,与现有方法相比,这些新方法在广泛的效应共享设置下具有快速和提高预测精度的优点。此外,在效果不共享的情况下,我们的方法仍然与最先进的方法具有竞争力。在基因型组织表达(GTEx)项目中表达数据的实际数据分析中,我们的方法平均提高了所有组织的预测性能,在效果强烈共享的组织和样本量较小的组织中收益最大。虽然我们使用基因表达预测来说明我们的方法,但这些方法通常适用于任何多表型应用,包括多基因评分和育种价值的预测。因此,我们的方法有潜力提供跨领域和生物体的改进。
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引用次数: 0
Relaxing parametric assumptions for non-linear Mendelian randomization using a doubly-ranked stratification method. 使用双排序分层法放宽非线性孟德尔随机化的参数假设。
IF 4.5 2区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2023-06-30 eCollection Date: 2023-06-01 DOI: 10.1371/journal.pgen.1010823
Haodong Tian, Amy M Mason, Cunhao Liu, Stephen Burgess

Non-linear Mendelian randomization is an extension to standard Mendelian randomization to explore the shape of the causal relationship between an exposure and outcome using an instrumental variable. A stratification approach to non-linear Mendelian randomization divides the population into strata and calculates separate instrumental variable estimates in each stratum. However, the standard implementation of stratification, referred to as the residual method, relies on strong parametric assumptions of linearity and homogeneity between the instrument and the exposure to form the strata. If these stratification assumptions are violated, the instrumental variable assumptions may be violated in the strata even if they are satisfied in the population, resulting in misleading estimates. We propose a new stratification method, referred to as the doubly-ranked method, that does not require strict parametric assumptions to create strata with different average levels of the exposure such that the instrumental variable assumptions are satisfied within the strata. Our simulation study indicates that the doubly-ranked method can obtain unbiased stratum-specific estimates and appropriate coverage rates even when the effect of the instrument on the exposure is non-linear or heterogeneous. Moreover, it can also provide unbiased estimates when the exposure is coarsened (that is, rounded, binned into categories, or truncated), a scenario that is common in applied practice and leads to substantial bias in the residual method. We applied the proposed doubly-ranked method to investigate the effect of alcohol intake on systolic blood pressure, and found evidence of a positive effect of alcohol intake, particularly at higher levels of alcohol consumption.

非线性孟德尔随机法是对标准孟德尔随机法的扩展,利用工具变量探索暴露与结果之间因果关系的形态。非线性孟德尔随机法的分层方法是将人群划分为若干层,并在每个层中计算单独的工具变量估计值。然而,分层的标准实施方法,即残差法,依赖于工具和暴露之间线性和同质性的强参数假设来形成分层。如果违反这些分层假设,即使在总体中满足工具变量假设,在分层中也可能违反工具变量假设,从而导致误导性估计。我们提出了一种新的分层方法,称为双重排序法,它不需要严格的参数假设,就能建立具有不同平均暴露水平的分层,从而在分层内满足工具变量假设。我们的模拟研究表明,即使工具对暴露的影响是非线性或异质性的,双排序法也能获得无偏的分层估计值和适当的覆盖率。此外,当暴露量被粗略化(即四舍五入、分门别类或截断)时,它也能提供无偏的估计值,这种情况在应用实践中很常见,会导致残差法产生很大偏差。我们应用所提出的双重排序法研究了酒精摄入量对收缩压的影响,发现有证据表明酒精摄入量有积极影响,尤其是在酒精摄入量较高的情况下。
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引用次数: 13
The CERV protein of Cer1, a C. elegans LTR retrotransposon, is required for nuclear export of viral genomic RNA and can form giant nuclear rods. 秀丽隐杆线虫 LTR 反转座子 Cer1 的 CERV 蛋白是病毒基因组 RNA 核输出所必需的,并能形成巨大的核棒。
IF 4.5 2区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2023-06-29 eCollection Date: 2023-06-01 DOI: 10.1371/journal.pgen.1010804
Bing Sun, Haram Kim, Craig C Mello, James R Priess

Retroviruses and closely related LTR retrotransposons export full-length, unspliced genomic RNA (gRNA) for packaging into virions and to serve as the mRNA encoding GAG and POL polyproteins. Because gRNA often includes splice acceptor and donor sequences used to splice viral mRNAs, retroelements must overcome host mechanisms that retain intron-containing RNAs in the nucleus. Here we examine gRNA expression in Cer1, an LTR retrotransposon in C. elegans which somehow avoids silencing and is highly expressed in germ cells. Newly exported Cer1 gRNA associates rapidly with the Cer1 GAG protein, which has structural similarity with retroviral GAG proteins. gRNA export requires CERV (C. elegans regulator of viral expression), a novel protein encoded by a spliced Cer1 mRNA. CERV phosphorylation at S214 is essential for gRNA export, and phosphorylated CERV colocalizes with nuclear gRNA at presumptive sites of transcription. By electron microscopy, tagged CERV proteins surround clusters of distinct, linear fibrils that likely represent gRNA molecules. Single fibrils, or groups of aligned fibrils, also localize near nuclear pores. During the C. elegans self-fertile period, when hermaphrodites fertilize oocytes with their own sperm, CERV concentrates in two nuclear foci that are coincident with gRNA. However, as hermaphrodites cease self-fertilization, and can only produce cross-progeny, CERV undergoes a remarkable transition to form giant nuclear rods or cylinders that can be up to 5 microns in length. We propose a novel mechanism of rod formation, in which stage-specific changes in the nucleolus induce CERV to localize to the nucleolar periphery in flattened streaks of protein and gRNA; these streaks then roll up into cylinders. The rods are a widespread feature of Cer1 in wild strains of C. elegans, but their function is not known and might be limited to cross-progeny. We speculate that the adaptive strategy Cer1 uses for the identical self-progeny of a host hermaphrodite might differ for heterozygous cross-progeny sired by males. For example, mating introduces male chromosomes which can have different, or no, Cer1 elements.

逆转录病毒和密切相关的 LTR 逆转录转座子输出全长、未剪接的基因组 RNA(gRNA),用于包装成病毒,并作为编码 GAG 和 POL 多聚蛋白的 mRNA。由于 gRNA 通常包括用于剪接病毒 mRNA 的剪接受体和供体序列,因此逆转录子必须克服宿主将含内含子 RNA 保留在细胞核中的机制。在这里,我们研究了Cer1中gRNA的表达,Cer1是优雅小鼠中的一种LTR逆转录质子,它能以某种方式避免沉默,并在生殖细胞中高度表达。新导出的 Cer1 gRNA 会迅速与 Cer1 GAG 蛋白结合,后者与逆转录病毒 GAG 蛋白结构相似。CERV 在 S214 处的磷酸化对 gRNA 的输出至关重要,磷酸化的 CERV 与核 gRNA 共同定位在推测的转录位点。通过电子显微镜观察,标记的 CERV 蛋白围绕着可能代表 gRNA 分子的独特线性纤维簇。单条纤维或排列整齐的纤维群也会出现在核孔附近。在秀丽隐杆线虫的自交期,即雌雄同体用自己的精子使卵母细胞受精时,CERV 集中在两个与 gRNA 重合的核病灶中。然而,当雌雄同体停止自交,只能产生杂交后代时,CERV 就会发生显著转变,形成长度可达 5 微米的巨大核棒或核柱。我们提出了一种新的核棒形成机制,即核仁中的阶段性特异性变化诱导 CERV 以扁平的蛋白质和 gRNA 条纹形式定位到核仁外围,然后这些条纹卷成圆柱体。这些条纹是野生品系 C. elegans 中 Cer1 的普遍特征,但其功能尚不清楚,可能仅限于杂交后代。我们推测,Cer1 对宿主雌雄同体的相同自交后代所采用的适应策略可能与雄性异交后代不同。例如,交配引入的雄性染色体可能具有不同的或没有 Cer1 元件。
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引用次数: 0
Rbf/E2F1 control growth and endoreplication via steroid-independent Ecdysone Receptor signalling in Drosophila prostate-like secondary cells. 在果蝇前列腺样次级细胞中,Rbf/E2F1通过类固醇无关的蜕皮激素受体信号控制生长和内复制。
IF 4.5 2区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2023-06-26 eCollection Date: 2023-06-01 DOI: 10.1371/journal.pgen.1010815
Aashika Sekar, Aaron Leiblich, S Mark Wainwright, Cláudia C Mendes, Dhruv Sarma, Josephine E E U Hellberg, Carina Gandy, Deborah C I Goberdhan, Freddie C Hamdy, Clive Wilson

In prostate cancer, loss of the tumour suppressor gene, Retinoblastoma (Rb), and consequent activation of transcription factor E2F1 typically occurs at a late-stage of tumour progression. It appears to regulate a switch to an androgen-independent form of cancer, castration-resistant prostate cancer (CRPC), which frequently still requires androgen receptor (AR) signalling. We have previously shown that upon mating, binucleate secondary cells (SCs) of the Drosophila melanogaster male accessory gland (AG), which share some similarities with prostate epithelial cells, switch their growth regulation from a steroid-dependent to a steroid-independent form of Ecdysone Receptor (EcR) control. This physiological change induces genome endoreplication and allows SCs to rapidly replenish their secretory compartments, even when ecdysone levels are low because the male has not previously been exposed to females. Here, we test whether the Drosophila Rb homologue, Rbf, and E2F1 regulate this switch. Surprisingly, we find that excess Rbf activity reversibly suppresses binucleation in adult SCs. We also demonstrate that Rbf, E2F1 and the cell cycle regulators, Cyclin D (CycD) and Cyclin E (CycE), are key regulators of mating-dependent SC endoreplication, as well as SC growth in both virgin and mated males. Importantly, we show that the CycD/Rbf/E2F1 axis requires the EcR, but not ecdysone, to trigger CycE-dependent endoreplication and endoreplication-associated growth in SCs, mirroring changes seen in CRPC. Furthermore, Bone Morphogenetic Protein (BMP) signalling, mediated by the BMP ligand Decapentaplegic (Dpp), intersects with CycD/Rbf/E2F1 signalling to drive endoreplication in these fly cells. Overall, our work reveals a signalling switch, which permits rapid growth of SCs and increased secretion after mating, independently of previous exposure to females. The changes observed share mechanistic parallels with the pathological switch to hormone-independent AR signalling seen in CRPC, suggesting that the latter may reflect the dysregulation of a currently unidentified physiological process.

在前列腺癌中,肿瘤抑制基因视网膜母细胞瘤(Rb)的缺失以及随之而来的转录因子 E2F1 的激活通常发生在肿瘤进展的晚期。它似乎调控着向雄激素依赖性癌症--阉割抗性前列腺癌(CRPC)--的转变,而这种癌症通常仍需要雄激素受体(AR)信号传导。我们之前已经证明,在交配时,与前列腺上皮细胞有某些相似之处的黑腹果蝇雄性附属腺(AG)的双核次细胞(SC)会将其生长调控从依赖类固醇的蜕皮激素受体(EcR)调控形式转换为不依赖类固醇的蜕皮激素受体(EcR)调控形式。这种生理变化会诱导基因组的内复制,并使SCs迅速补充其分泌区,即使在蜕皮激素水平较低的情况下也是如此,因为雄性之前没有接触过雌性。在这里,我们测试了果蝇的 Rb 同源物 Rbf 和 E2F1 是否调控这种转换。令人惊讶的是,我们发现过量的 Rbf 活性会可逆地抑制成体 SC 中的双核形成。我们还证明,Rbf、E2F1 和细胞周期调节因子 Cyclin D(CycD)和 Cyclin E(CycE)是交配依赖性 SC 内再复制的关键调节因子,也是处女雄性和交配雄性 SC 生长的关键调节因子。重要的是,我们发现CycD/Rbf/E2F1轴需要EcR而不是蜕皮激素来触发依赖CycE的内再复制以及SC中与内再复制相关的生长,这反映了CRPC中的变化。此外,骨形态发生蛋白(BMP)信号与CycD/Rbf/E2F1信号相互交织,由BMP配体十日瘫(Dpp)介导,驱动这些蝇细胞的内再复制。总之,我们的研究揭示了一种信号开关,它允许 SCs 在交配后快速生长并增加分泌,而与之前暴露于雌性无关。观察到的变化与 CRPC 中出现的依赖激素的 AR 信号的病理转换有着相似的机理,这表明后者可能反映了一种目前尚未确定的生理过程失调。
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引用次数: 0
A monocarboxylate transporter rescues frontotemporal dementia and Alzheimer’s disease models 一种单羧酸转运蛋白拯救额颞叶痴呆和阿尔茨海默病模型
IF 4.5 2区 生物学 Q1 Agricultural and Biological Sciences Pub Date : 2023-06-26 DOI: 10.1101/2023.06.25.546435
Dongwei Xu, Alec J. Vincent, Andrés González-Gutiérrez, Benjamin Aleyakpo, S. Anoar, Ashling Giblin, M. Atilano, M. Adams, Dunxin Shen, A. Thoeng, Elli Tsintzas, Marie Maeland, A. Isaacs, J. Sierralta, Teresa Niccoli
Brains are highly metabolically active organs, consuming 20% of an organisms’ energy at resting state. A decline in glucose metabolism is a common feature across a number of neurodegenerative diseases. Another common feature is the progressive accumulation of insoluble protein deposits, it’s unclear if the two are linked. Glucose metabolism in the brain is highly coupled between neurons and glia, with glucose taken up by glia and metabolised to lactate, which is then shuttled via transporters to neurons, where it is converted back to pyruvate and fed into the TCA cycle for ATP production. Monocarboxylates are also involved in signalling, and play broad ranging roles in brain homeostasis and metabolic reprogramming. However, the role of monocarboxylates in dementia has not been tested. Here, we find that increasing pyruvate import in Drosophila neurons by over-expression of the transporter bumpel, leads to a rescue of lifespan and behavioural phenotypes in fly models of both frontotemporal dementia and Alzheimer’s disease. The rescue is linked to a clearance of late stage autolysosomes, leading to degradation of toxic peptides associated with disease. We propose upregulation of pyruvate import into neurons as potentially a broad-scope therapeutic approach to increase neuronal autophagy, which could be beneficial for multiple dementias.
大脑是新陈代谢非常活跃的器官,在静息状态下消耗生物体20%的能量。葡萄糖代谢下降是许多神经退行性疾病的共同特征。另一个共同特征是不溶性蛋白质沉积物的逐渐积累,目前尚不清楚这两者是否有联系。大脑中的葡萄糖代谢在神经元和神经胶质之间是高度耦合的,葡萄糖被神经胶质吸收并代谢成乳酸,然后通过转运体穿梭到神经元,在那里它被转化回丙酮酸,并进入三羧酸循环以产生ATP。单羧酸盐也参与信号传导,并在大脑稳态和代谢重编程中发挥广泛作用。然而,单羧酸盐在痴呆症中的作用尚未得到测试。在这里,我们发现通过转运蛋白bumpel的过度表达增加果蝇神经元中丙酮酸的进口,导致额颞叶痴呆和阿尔茨海默病的果蝇模型的寿命和行为表型的拯救。这种拯救与晚期自溶酶体的清除有关,导致与疾病相关的有毒肽的降解。我们建议上调丙酮酸输入神经元作为一种潜在的广泛的治疗方法来增加神经元自噬,这可能对多发性痴呆有益。
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