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Technology to the rescue: how to uncover the role of transposable elements in preimplantation development. 技术拯救:如何揭示转座元件在植入前发育中的作用。
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-26 DOI: 10.1042/BST20231262
Lauryn A Deaville, Rebecca V Berrens

Transposable elements (TEs) are highly expressed in preimplantation development. Preimplantation development is the phase when the cells of the early embryo undergo the first cell fate choice and change from being totipotent to pluripotent. A range of studies have advanced our understanding of TEs in preimplantation, as well as their epigenetic regulation and functional roles. However, many questions remain about the implications of TE expression during early development. Challenges originate first due to the abundance of TEs in the genome, and second because of the limited cell numbers in preimplantation. Here we review the most recent technological advancements promising to shed light onto the role of TEs in preimplantation development. We explore novel avenues to identify genomic TE insertions and improve our understanding of the regulatory mechanisms and roles of TEs and their RNA and protein products during early development.

可转座元件(TE)在胚胎植入前的发育过程中高度表达。胚胎植入前发育是早期胚胎细胞进行第一次细胞命运选择并从全能细胞转变为多能细胞的阶段。一系列研究加深了我们对植入前发育过程中 TEs 及其表观遗传调控和功能作用的了解。然而,关于 TE 表达在早期发育过程中的影响仍存在许多问题。首先,基因组中存在大量 TE,其次,胚胎植入前的细胞数量有限,这些都是面临挑战的原因。在此,我们回顾了有望揭示 TE 在植入前发育中作用的最新技术进展。我们将探索识别基因组 TE 插入的新途径,加深我们对 TE 及其 RNA 和蛋白质产物在早期发育过程中的调控机制和作用的理解。
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引用次数: 0
Nucleosomal asymmetry: a novel mechanism to regulate nucleosome function. 核小体不对称:调节核小体功能的新机制
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-26 DOI: 10.1042/BST20230877
Devisree Valsakumar, Philipp Voigt

Nucleosomes constitute the fundamental building blocks of chromatin. They are comprised of DNA wrapped around a histone octamer formed of two copies each of the four core histones H2A, H2B, H3, and H4. Nucleosomal histones undergo a plethora of posttranslational modifications that regulate gene expression and other chromatin-templated processes by altering chromatin structure or by recruiting effector proteins. Given their symmetric arrangement, the sister histones within a nucleosome have commonly been considered to be equivalent and to carry the same modifications. However, it is now clear that nucleosomes can exhibit asymmetry, combining differentially modified sister histones or different variants of the same histone within a single nucleosome. Enabled by the development of novel tools that allow generating asymmetrically modified nucleosomes, recent biochemical and cell-based studies have begun to shed light on the origins and functional consequences of nucleosomal asymmetry. These studies indicate that nucleosomal asymmetry represents a novel regulatory mechanism in the establishment and functional readout of chromatin states. Asymmetry expands the combinatorial space available for setting up complex sets of histone marks at individual nucleosomes, regulating multivalent interactions with histone modifiers and readers. The resulting functional consequences of asymmetry regulate transcription, poising of developmental gene expression by bivalent chromatin, and the mechanisms by which oncohistones deregulate chromatin states in cancer. Here, we review recent progress and current challenges in uncovering the mechanisms and biological functions of nucleosomal asymmetry.

核小体是染色质的基本组成部分。核小体由 DNA 组成,外面包着组蛋白八聚体,组蛋白八聚体由四种核心组蛋白 H2A、H2B、H3 和 H4 各两份组成。核糖体组蛋白经过大量的翻译后修饰,通过改变染色质结构或招募效应蛋白来调节基因表达和其他染色质引发的过程。鉴于核小体的对称排列,核小体内的姐妹组蛋白通常被认为是等同的,并携带相同的修饰。然而,现在已经很清楚,核小体可以表现出不对称性,在单个核小体内结合了不同修饰的姐妹组蛋白或同一组蛋白的不同变体。由于开发出了可生成不对称修饰核小体的新型工具,最近的生化研究和基于细胞的研究已开始揭示核小体不对称的起源和功能性后果。这些研究表明,核小体不对称是染色质状态建立和功能读出的一种新型调控机制。不对称性扩大了可用于在单个核小体上建立复杂组蛋白标记集的组合空间,调节了与组蛋白修饰物和阅读器的多价相互作用。由此产生的不对称功能性后果可调节转录、二价染色质对发育基因表达的调控,以及共价组蛋白对癌症染色质状态的失调机制。在此,我们回顾了在揭示核小体不对称的机制和生物学功能方面的最新进展和当前挑战。
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引用次数: 0
Making the leap from technique to treatment - genetic engineering is paving the way for more efficient phage therapy. 从技术到治疗的飞跃--基因工程正在为更有效的噬菌体疗法铺平道路。
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-26 DOI: 10.1042/BST20231289
Jessica M Lewis, Joshua Williams, Antonia P Sagona

Bacteriophages (phages) are viruses specific to bacteria that target them with great efficiency and specificity. Phages were first studied for their antibacterial potential in the early twentieth century; however, their use was largely eclipsed by the popularity of antibiotics. Given the surge of antimicrobial-resistant strains worldwide, there has been a renaissance in harnessing phages as therapeutics once more. One of the key advantages of phages is their amenability to modification, allowing the generation of numerous derivatives optimised for specific functions depending on the modification. These enhanced derivatives could display higher infectivity, expanded host range or greater affinity to human tissues, where some bacterial species exert their pathogenesis. Despite this, there has been a noticeable discrepancy between the generation of derivatives in vitro and their clinical application in vivo. In most instances, phage therapy is only used on a compassionate-use basis, where all other treatment options have been exhausted. A lack of clinical trials and numerous regulatory hurdles hamper the progress of phage therapy and in turn, the engineered variants, in becoming widely used in the clinic. In this review, we outline the various types of modifications enacted upon phages and how these modifications contribute to their enhanced bactericidal function compared with wild-type phages. We also discuss the nascent progress of genetically modified phages in clinical trials along with the current issues these are confronted with, to validate it as a therapy in the clinic.

噬菌体(噬菌体)是针对细菌的特异性病毒,能高效、特异地攻击细菌。早在二十世纪初,人们就开始研究噬菌体的抗菌潜力;然而,随着抗生素的普及,噬菌体的应用在很大程度上黯然失色。随着全球抗生素耐药菌株的激增,利用噬菌体进行治疗的热潮再次兴起。噬菌体的主要优势之一是易于改造,可以根据改造情况生成许多具有特定功能的优化衍生物。这些增强型衍生物可以显示出更高的感染性、更广的宿主范围或对人体组织更强的亲和力,而某些细菌物种正是在人体组织中发挥致病作用的。尽管如此,体外衍生物的产生与体内的临床应用之间仍存在明显差异。在大多数情况下,噬菌体疗法只是在所有其他治疗方法都已用尽的情况下,出于同情才使用。缺乏临床试验和众多监管障碍阻碍了噬菌体疗法的发展,进而阻碍了工程变体在临床上的广泛应用。在这篇综述中,我们概述了噬菌体的各种修饰类型,以及这些修饰如何使噬菌体的杀菌功能比野生型噬菌体更强。我们还讨论了转基因噬菌体在临床试验中取得的新进展,以及目前面临的问题,以便将其作为一种疗法应用于临床。
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引用次数: 0
Retrotransposons in embryogenesis and neurodevelopment. 胚胎发生和神经发育中的逆转录载体
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-26 DOI: 10.1042/BST20230757
Mary Jo Talley, Michelle S Longworth

Retrotransposable elements (RTEs) are genetic elements that can replicate and insert new copies into different genomic locations. RTEs have long been identified as 'parasitic genes', as their mobilization can cause mutations, DNA damage, and inflammation. Interestingly, high levels of retrotransposon activation are observed in early embryogenesis and neurodevelopment, suggesting that RTEs may possess functional roles during these stages of development. Recent studies demonstrate that RTEs can function as transcriptional regulatory elements through mechanisms such as chromatin organization and noncoding RNAs. It is clear, however, that RTE expression and activity must be restrained at some level during development, since overactivation of RTEs during neurodevelopment is associated with several developmental disorders. Further investigation is needed to understand the importance of RTE expression and activity during neurodevelopment and the balance between RTE-regulated development and RTE-mediated pathogenesis.

逆转录可逆元件(RTE)是一种可复制并在不同基因组位置插入新拷贝的遗传元件。RTE 长期以来一直被认为是 "寄生基因",因为它们的移动会导致突变、DNA 损伤和炎症。有趣的是,在早期胚胎发育和神经发育过程中观察到高水平的逆转录转座子活化,这表明 RTE 在这些发育阶段可能具有功能性作用。最近的研究表明,RTE 可通过染色质组织和非编码 RNA 等机制发挥转录调控元件的功能。然而,很明显,RTE 的表达和活性在发育过程中必须受到一定程度的抑制,因为神经发育过程中 RTE 的过度激活与多种发育障碍有关。要了解神经发育过程中 RTE 表达和活性的重要性,以及 RTE 调节的发育和 RTE 介导的发病机制之间的平衡,还需要进一步的研究。
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引用次数: 0
Reconstituting membrane fission using a high content and throughput assay. 利用高含量和高通量测定法重建膜裂变。
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-26 DOI: 10.1042/BST20231325
Uma Swaminathan, Thomas J Pucadyil

Protein-mediated membrane fission has been analyzed both in bulk and at the single event resolution. Studies on membrane fission in vitro using tethers have provided fundamental insights into the process but are low in throughput. In recent years, supported membrane template (SMrT) have emerged as a facile and convenient assay system for membrane fission. SMrTs provide useful information on intermediates in the pathway to fission and are therefore high in content. They are also high in throughput because numerous fission events can be monitored in a single experiment. This review discusses the utility of SMrTs in providing insights into fission pathways and its adaptation to annotate membrane fission functions in proteins.

对蛋白质介导的膜裂变进行了批量和单个事件的分析。使用系链对体外膜裂变进行的研究提供了对这一过程的基本认识,但其通量较低。近年来,支撑膜模板(SMrT)已成为一种简便易行的膜裂变检测系统。SMrT 提供了裂变途径中中间产物的有用信息,因此含量很高。它们的通量也很高,因为在一次实验中可以监测到许多裂变事件。本综述将讨论 SMrTs 在深入了解裂变途径方面的效用,以及它在注释蛋白质的膜裂变功能方面的适应性。
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引用次数: 0
Viral genome sequencing methods: benefits and pitfalls of current approaches. 病毒基因组测序方法:当前方法的优势和缺陷。
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-26 DOI: 10.1042/BST20231322
Natasha Jansz, Geoffrey J Faulkner

Whole genome sequencing of viruses provides high-resolution molecular insights, enhancing our understanding of viral genome function and phylogeny. Beyond fundamental research, viral sequencing is increasingly vital for pathogen surveillance, epidemiology, and clinical applications. As sequencing methods rapidly evolve, the diversity of viral genomics applications and catalogued genomes continues to expand. Advances in long-read, single molecule, real-time sequencing methodologies present opportunities to sequence contiguous, haplotype resolved viral genomes in a range of research and applied settings. Here we present an overview of nucleic acid sequencing methods and their applications in studying viral genomes. We emphasise the advantages of different viral sequencing approaches, with a particular focus on the benefits of third-generation sequencing technologies in elucidating viral evolution, transmission networks, and pathogenesis.

病毒的全基因组测序提供了高分辨率的分子洞察力,增强了我们对病毒基因组功能和系统发育的了解。除基础研究外,病毒测序对病原体监测、流行病学和临床应用也越来越重要。随着测序方法的快速发展,病毒基因组学应用和编目基因组的多样性也在不断扩大。长读程、单分子、实时测序方法的进步为在一系列研究和应用环境中对连续、单体型解析的病毒基因组进行测序提供了机会。在此,我们将概述核酸测序方法及其在病毒基因组研究中的应用。我们强调不同病毒测序方法的优势,尤其关注第三代测序技术在阐明病毒进化、传播网络和致病机理方面的优势。
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引用次数: 0
Modification of extracellular matrix proteins by oxidants and electrophiles. 氧化剂和亲电物对细胞外基质蛋白质的修饰。
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-26 DOI: 10.1042/BST20230860
Karen C Yang-Jensen, Sara M Jørgensen, Christine Y Chuang, Michael J Davies

The extracellular matrix (ECM) is critical to biological architecture and determines cellular properties, function and activity. In many situations it is highly abundant, with collagens and elastin being some of the most abundant proteins in mammals. The ECM comprises of multiple different protein species and sugar polymers, with both different isoforms and post-translational modifications (PTMs) providing a large variety of microenvironments that play a key role in determining tissue structure and health. A number of the PTMs (e.g. cross-links) present in the ECM are critical to integrity and function, whereas others are deleterious to both ECM structure and associated cells. Modifications induced by reactive oxidants and electrophiles have been reported to accumulate in some ECM with increasing age. This accumulation can be exacerbated by disease, and in particular those associated with acute or chronic inflammation, obesity and diabetes. This is likely to be due to higher fluxes of modifying agents in these conditions. In this focused review, the role and effects of oxidants and other electrophiles on ECM are discussed, with a particular focus on the artery wall and atherosclerotic cardiovascular disease. Modifications generated on ECM components are reviewed, together with the effects of these species on cellular properties including adhesion, proliferation, migration, viability, metabolic activity, gene expression and phenotype. Increasing data indicates that ECM modifications are both prevalent in human and mammalian tissues and play an important role in disease development and progression.

细胞外基质(ECM)对生物结构至关重要,并决定着细胞的特性、功能和活性。在许多情况下,它的含量都很高,胶原蛋白和弹性蛋白是哺乳动物体内含量最高的蛋白质。ECM 由多种不同的蛋白质和糖聚合物组成,具有不同的异构体和翻译后修饰 (PTM),提供了多种微环境,在决定组织结构和健康方面发挥着关键作用。ECM 中存在的一些 PTM(如交联)对其完整性和功能至关重要,而其他一些 PTM 则对 ECM 结构和相关细胞有害。据报道,随着年龄的增长,活性氧化剂和亲电物诱导的修饰会在某些 ECM 中积累。疾病,尤其是与急性或慢性炎症、肥胖和糖尿病相关的疾病,会加剧这种积累。这可能是由于在这些情况下改性剂的通量较高。在这篇重点综述中,讨论了氧化剂和其他嗜电物对 ECM 的作用和影响,尤其侧重于动脉壁和动脉粥样硬化性心血管疾病。文章回顾了 ECM 成分上产生的修饰,以及这些物质对细胞特性的影响,包括粘附、增殖、迁移、存活能力、代谢活动、基因表达和表型。越来越多的数据表明,ECM 修饰在人类和哺乳动物组织中普遍存在,并在疾病的发生和发展中发挥着重要作用。
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引用次数: 0
The role of Matrin-3 in physiology and its dysregulation in disease. Matrin-3 在生理学中的作用及其在疾病中的失调。
IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-26 DOI: 10.1042/BST20220585
Macy L Sprunger, Meredith E Jackrel

The dysfunction of many RNA-binding proteins (RBPs) that are heavily disordered, including TDP-43 and FUS, are implicated in amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). These proteins serve many important roles in the cell, and their capacity to form biomolecular condensates (BMCs) is key to their function, but also a vulnerability that can lead to misregulation and disease. Matrin-3 (MATR3) is an intrinsically disordered RBP implicated both genetically and pathologically in ALS/FTD, though it is relatively understudied as compared with TDP-43 and FUS. In addition to binding RNA, MATR3 also binds DNA and is implicated in many cellular processes including the DNA damage response, transcription, splicing, and cell differentiation. It is unclear if MATR3 localizes to BMCs under physiological conditions, which is brought further into question due to its lack of a prion-like domain. Here, we review recent studies regarding MATR3 and its roles in numerous physiological processes, as well as its implication in a range of diseases.

肌萎缩侧索硬化症和额颞叶痴呆症(ALS/FTD)与许多严重紊乱的 RNA 结合蛋白(RBPs)(包括 TDP-43 和 FUS)的功能障碍有关。这些蛋白质在细胞中发挥着许多重要作用,它们形成生物分子凝聚物(BMC)的能力是其功能的关键,但也是导致误调和疾病的一个弱点。Matrin-3(MATR3)是一种内在紊乱的 RBP,与 ALS/FTD 的遗传学和病理学都有关联,但与 TDP-43 和 FUS 相比,对它的研究相对较少。除了结合 RNA 外,MATR3 还结合 DNA,并与许多细胞过程有关,包括 DNA 损伤反应、转录、剪接和细胞分化。目前还不清楚 MATR3 在生理条件下是否会定位到 BMC,由于它缺乏朊病毒样结构域,这一点就更成问题了。在此,我们回顾了有关 MATR3 及其在众多生理过程中的作用以及在一系列疾病中的影响的最新研究。
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引用次数: 0
The choreography of chromatin in RNA polymerase III regulation. 染色质在 RNA 聚合酶 III 调控中的作用。
IF 3.9 3区 生物学 Q2 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-04-26 DOI: 10.1042/BST20230770
Maria Elize van Breugel, Alan Gerber, Fred van Leeuwen
Regulation of eukaryotic gene expression involves a dynamic interplay between the core transcriptional machinery, transcription factors, and chromatin organization and modification. While this applies to transcription by all RNA polymerase complexes, RNA polymerase III (RNAPIII) seems to be atypical with respect to its mechanisms of regulation. One distinctive feature of most RNAPIII transcribed genes is that they are devoid of nucleosomes, which relates to the high levels of transcription. Moreover, most of the regulatory sequences are not outside but within the transcribed open chromatin regions. Yet, several lines of evidence suggest that chromatin factors affect RNAPIII dynamics and activity and that gene sequence alone does not explain the observed regulation of RNAPIII. Here we discuss the role of chromatin modification and organization of RNAPIII transcribed genes and how they interact with the core transcriptional RNAPIII machinery and regulatory DNA elements in and around the transcribed genes.
真核生物基因表达的调控涉及核心转录机制、转录因子以及染色质组织和修饰之间的动态相互作用。虽然这适用于所有 RNA 聚合酶复合体的转录,但 RNA 聚合酶 III(RNAPIII)的调控机制似乎并不典型。大多数 RNAPIII 转录基因的一个显著特点是没有核小体,这与高水平的转录有关。此外,大多数调控序列并不在转录的开放染色质区域之外,而是在该区域之内。然而,一些证据表明,染色质因子会影响 RNAPIII 的动态和活性,基因序列本身并不能解释所观察到的 RNAPIII 的调控。在此,我们将讨论染色质修饰和 RNAPIII 转录基因组织的作用,以及它们如何与 RNAPIII 核心转录机制和转录基因内部及周围的 DNA 调控元件相互作用。
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引用次数: 0
Raman spectroscopy in the study of amyloid formation and phase separation. 拉曼光谱在淀粉样蛋白形成和相分离研究中的应用。
IF 3.9 3区 生物学 Q2 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-04-26 DOI: 10.1042/BST20230599
Sashary Ramos, Jennifer C Lee
Neurodegenerative diseases, such as Alzheimer's and Parkinson's, share a common pathological feature of amyloid structure accumulation. However, the structure-function relationship between these well-ordered, β-sheet-rich, filamentous protein deposits and disease etiology remains to be defined. Recently, an emerging hypothesis has linked phase separation, a process involved in the formation of protein condensates, to amyloid formation, suggesting that liquid protein droplets serve as loci for amyloid initiation. To elucidate how these processes contribute to disease progression, tools that can directly report on protein secondary structural changes are needed. Here, we review recent studies that have demonstrated Raman spectroscopy as a powerful vibrational technique for interrogating amyloid structures; one that offers sensitivity from the global secondary structural level to specific residues. This probe-free technique is further enhanced via coupling to a microscope, which affords structural data with spatial resolution, known as Raman spectral imaging (RSI). In vitro and in cellulo applications of RSI are discussed, highlighting studies of protein droplet aging, cellular internalization of fibrils, and Raman imaging of intracellular water. Collectively, utilization of the myriad Raman spectroscopic methods will contribute to a deeper understanding of protein conformational dynamics in the complex cellular milieu and offer potential clinical diagnostic capabilities for protein misfolding and aggregation processes in disease states.
阿尔茨海默氏症和帕金森氏症等神经退行性疾病的共同病理特征是淀粉样蛋白结构的累积。然而,这些井然有序、富含β片的丝状蛋白沉积物与疾病病因之间的结构-功能关系仍有待明确。最近,一种新出现的假说将蛋白质凝聚物的形成过程--相分离与淀粉样蛋白的形成联系起来,认为液态蛋白质液滴是淀粉样蛋白的起始位置。要阐明这些过程是如何导致疾病进展的,需要能直接报告蛋白质二级结构变化的工具。在此,我们回顾了近期的研究,这些研究证明拉曼光谱是一种强大的振动技术,可用于检测淀粉样蛋白结构;该技术可提供从整体二级结构水平到特定残基的灵敏度。这种无需探针的技术通过与显微镜的耦合得到了进一步增强,从而提供了具有空间分辨率的结构数据,即拉曼光谱成像(RSI)。本文讨论了 RSI 在体外和细胞内的应用,重点研究了蛋白质液滴老化、纤维的细胞内化以及细胞内水的拉曼成像。总之,利用各种拉曼光谱方法将有助于加深对复杂细胞环境中蛋白质构象动态的理解,并为疾病状态下的蛋白质错误折叠和聚集过程提供潜在的临床诊断能力。
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