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R-loops in neurodegeneration 神经变性中的 R 环
IF 3.7 2区 生物学 Q2 CELL BIOLOGY
Current Opinion in Genetics & Development
Pub Date : 2025-04-08 DOI: 10.1016/j.gde.2025.102345
Chiara Beghѐ, Helena Harpham, Yasmine Barberic, Natalia Gromak
Neurodegenerative diseases are associated with the progressive loss of neurons. R-loops are non-canonical nucleic acid structures formed during transcription and composed of an RNA/DNA hybrid and a displaced single-stranded DNA. Whilst R-loops are important regulators of cellular processes, they are also associated with the pathologies of multiple disorders, including repeat expansion, motor neuron, inflammatory and ageing diseases. In this review, we discuss how R-loops contribute to pathological mechanisms that underpin neurodegeneration. We highlight the role of R-loops in several hallmarks of neurodegenerative disorders, including RNA and DNA defects, DNA damage, protein aggregation, inflammation, mitochondrial dysfunction, and neuronal cell death. We also discuss the potential role of R-loops as therapeutic targets for neurodegenerative disorders.
神经退行性疾病与神经元的逐渐丧失有关。r环是转录过程中形成的非规范核酸结构，由RNA/DNA杂交和移位的单链DNA组成。虽然r环是细胞过程的重要调节因子，但它们也与多种疾病的病理有关，包括重复扩张、运动神经元、炎症和衰老疾病。在这篇综述中，我们讨论了r环如何促进神经退行性变的病理机制。我们强调了r环在神经退行性疾病的几个标志中的作用，包括RNA和DNA缺陷、DNA损伤、蛋白质聚集、炎症、线粒体功能障碍和神经元细胞死亡。我们还讨论了r环作为神经退行性疾病治疗靶点的潜在作用。
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引用次数: 0
Reshaping transcription and translation dynamics during the awakening of the zygotic genome 在合子基因组觉醒期间重塑转录和翻译动力学
IF 3.7 2区 生物学 Q2 CELL BIOLOGY
Current Opinion in Genetics & Development
Pub Date : 2025-04-05 DOI: 10.1016/j.gde.2025.102344
Louise Maillard , Pierre Bensidoun , Mounia Lagha
During the oocyte-to-embryo transition, the transcriptome and proteome are dramatically reshaped. This transition entails a shift from maternally inherited mRNAs to newly synthesized transcripts, produced during the zygotic genome activation (ZGA). Furthermore, a crucial transcription and translation selectivity is required for early embryonic development. Studies across various model organisms have revealed conserved cis- and trans-regulatory mechanisms dictating the regimes by which mRNA and proteins are produced during this critical phase. In this article, we highlight recent technological and conceptual advances that deepen our understanding of how the tuning of both transcription and translation evolves during ZGA.
在卵母细胞向胚胎转变的过程中，转录组和蛋白质组发生了戏剧性的重塑。这种转变需要从母系遗传mrna到在合子基因组激活（ZGA）期间产生的新合成转录物的转变。此外，早期胚胎发育需要关键的转录和翻译选择性。对各种模式生物的研究揭示了保守的顺式和反式调节机制，这些机制决定了mRNA和蛋白质在这一关键阶段产生的机制。在本文中，我们强调了最近的技术和概念上的进步，这些进步加深了我们对ZGA期间转录和翻译的调整如何演变的理解。
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引用次数: 0
To splice or not to splice: pseudoexons in neurological disease and opportunities for intervention 剪接或不剪接：神经系统疾病中的假外显子及其干预机会
IF 3.7 2区 生物学 Q2 CELL BIOLOGY
Current Opinion in Genetics & Development
Pub Date : 2025-03-29 DOI: 10.1016/j.gde.2025.102343
Sue Fletcher , Niall P Keegan , Rita Mejzini , Ianthe L Pitout
Accurate exon selection and processing of pre-messenger RNA are crucial for normal gene expression. Mutations that alter splicing disrupt pre-mRNA processing and can have diverse effects on transcript structure, making the consequences of many such mutations difficult to predict. While next-generation sequencing technologies have transformed genetic diagnosis for many patients, deep intronic variants generally evade detection and characterisation. Of all the known types of splicing mutations, the most elusive to predict are those that activate pseudoexons. Because transcripts that contain pseudoexons are otherwise generally intact, exclusion (or ‘skipping’) of the pseudoexon during processing of the pre-mRNA is likely to generate a normal, functional mRNA. Characterisation of pseudoexon mutations will open opportunities for the development of antisense oligonucleotide strategies to overcome these disease-causing mutations.
准确的外显子选择和前信使RNA的加工对正常基因表达至关重要。改变剪接的突变会破坏前mrna的加工，并可能对转录本结构产生不同的影响，使得许多此类突变的后果难以预测。虽然下一代测序技术已经改变了许多患者的遗传诊断，但深层内含子变异通常逃避检测和表征。在所有已知的剪接突变类型中，最难以预测的是那些激活假外显子的剪接突变。由于含有假外显子的转录本通常是完整的，因此在预处理前mRNA过程中排除（或“跳过”）假外显子可能会产生正常的、功能性的mRNA。伪外显子突变的特征将为开发反义寡核苷酸策略来克服这些致病突变提供机会。
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引用次数: 0
The human endometrium: atlases, models, and prospects 人类子宫内膜：地图集、模型和前景
IF 3.7 2区 生物学 Q2 CELL BIOLOGY
Current Opinion in Genetics & Development
Pub Date : 2025-03-27 DOI: 10.1016/j.gde.2025.102341
Frederick CK Wong , Christina E Kim , Luz Garcia-Alonso , Roser Vento-Tormo
Approximately every month, the human endometrium undergoes a cycle of proliferation, differentiation, and, in the absence of pregnancy, shedding and repair. Each cycle relies on intricate interorgan coordination of hormonal secretions. Endometrial dysfunction causes significant health complications, including abnormal menstrual bleeding and endometriosis. However, effective diagnosis and treatments are hampered by understudied aetiology. Recent single-cell profiling has disentangled the diverse and dynamic nature of the endometrium, revealing regulatory roles of WNT, NOTCH, and TGFβ signalling. These insights have informed mechanistic studies enabled by advanced in vitro models that capture endometrial cellular heterogeneity and structure. In this review, we outline key single-cell transcriptomics atlases and models that provided new avenues for studying endometrial biology, discuss their limitations, and propose future directions.
大约每个月，人类子宫内膜都会经历一个增殖、分化的循环，在没有怀孕的情况下，还会经历脱落和修复。每个周期都依赖于复杂的器官间荷尔蒙分泌的协调。子宫内膜功能障碍导致严重的健康并发症，包括月经异常出血和子宫内膜异位症。然而，有效的诊断和治疗受到病因研究不足的阻碍。最近的单细胞分析揭示了子宫内膜的多样性和动态性，揭示了WNT、NOTCH和TGFβ信号的调节作用。这些见解为通过先进的体外模型捕获子宫内膜细胞异质性和结构的机制研究提供了信息。在这篇综述中，我们概述了关键的单细胞转录组学图谱和模型，为研究子宫内膜生物学提供了新的途径，讨论了它们的局限性，并提出了未来的方向。
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引用次数: 0
Recent advances in RNA-based therapeutics for neurodevelopmental disorders 基于rna的神经发育障碍治疗的最新进展
IF 3.7 2区 生物学 Q2 CELL BIOLOGY
Current Opinion in Genetics & Development
Pub Date : 2025-03-21 DOI: 10.1016/j.gde.2025.102339
Harini P Tirumala , Huda Y Zoghbi
A significant proportion of neurodevelopmental disorders (NDDs) are caused by gain-of-function (GOF) or loss-of-function (LOF) of specific genes. Strategies to normalize disease gene expression offer therapeutic potential for these disorders. The success and approval of RNA-based therapeutics for various disorders have led to a surge in RNA-based therapeutic research for NDDs with antisense oligonucleotides leading the field. This review discusses recent advances in therapeutic strategies that target pre-mRNA or mRNA for GOF and LOF NDDs that have promising preclinical evidence. These developments highlight important considerations and exciting future avenues for the development of therapies for NDDs.
很大一部分神经发育障碍（ndd）是由特定基因的功能获得（GOF）或功能丧失（LOF）引起的。使疾病基因表达正常化的策略为这些疾病提供了治疗潜力。基于rna的各种疾病治疗方法的成功和批准，导致了以反义寡核苷酸为主导的基于rna的ndd治疗研究的激增。本文综述了以pre-mRNA或mRNA为靶点的GOF和LOF ndd治疗策略的最新进展，这些策略具有良好的临床前证据。这些发展突出了ndd治疗发展的重要考虑和令人兴奋的未来途径。
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引用次数: 0
Alternative splicing in addiction 成瘾中的选择性剪接
IF 3.7 2区 生物学 Q2 CELL BIOLOGY
Current Opinion in Genetics & Development
Pub Date : 2025-03-19 DOI: 10.1016/j.gde.2025.102340
Akanksha Bhatnagar , Elizabeth A Heller
Addiction is a chronic and relapsing medical condition characterized by the compulsive use of drugs or alcohol despite harmful consequences. While transcriptional regulation has long been recognized for its role in addiction, recent genome-wide analyses have uncovered widespread alternative splicing changes that shift protein isoform diversity in multiple brain reward regions central to addiction. In this review, we discuss emerging research and evidence that alternative splicing is dysregulated in cocaine, alcohol, and opioid use disorders.
成瘾是一种慢性和反复发作的疾病，其特征是不顾有害后果而强迫使用药物或酒精。虽然转录调控长期以来一直被认为在成瘾中发挥作用，但最近的全基因组分析发现，广泛存在的选择性剪接变化改变了多个大脑奖励区域中蛋白质异构体的多样性，这些区域与成瘾有关。在这篇综述中，我们讨论了在可卡因、酒精和阿片类药物使用障碍中选择性剪接失调的新研究和证据。
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引用次数: 0
Totipotency or plenipotency: rethinking stem cell bipotentiality 全能性或全能性：重新思考干细胞的双潜能性
IF 3.7 2区 生物学 Q2 CELL BIOLOGY
Current Opinion in Genetics & Development
Pub Date : 2025-03-19 DOI: 10.1016/j.gde.2025.102342
Duancheng Wen , Jianlong Wang
The term ‘totipotency’ has often been misapplied in stem cell research to describe cells with embryonic and extraembryonic bipotentiality, despite a lack of evidence that they can generate an entire organism from a single cell. Additionally, no specific term currently distinguishes bipotential stem cells from pluripotent cells, which contribute poorly to extraembryonic tissues. This review examines the developmental continuum from totipotency to pluripotency in early embryos and revisits the previously proposed concept of plenipotency in preimplantation development. We evaluate emerging stem cell models that exhibit bipotentiality but have lost the ability to autonomously initiate and sustain the sequential fate decisions necessary to develop into a complete organism. Unlike totipotent embryonic cells, which retain the information required to initiate fate decisions at the correct timing and cell numbers, these stem cells have lost that capacity. This loss of critical developmental information distinguishes totipotency from plenipotency, with bipotential stem cells aligning more closely with the latter. By distinguishing plenipotency from totipotency and pluripotency, we aim to refine terminology, enhance our understanding of early embryonic development, and address ethical considerations in human research.
在干细胞研究中，“全能性”一词经常被误用来描述具有胚胎和胚胎外双潜能的细胞，尽管缺乏证据表明它们可以从单个细胞产生整个生物体。此外，目前还没有专门的术语来区分双潜能干细胞和多能细胞，后者对胚胎外组织的贡献很小。本文回顾了早期胚胎从全能性到多能性的发育过程，并回顾了以前提出的胚胎着床前发育的全能性概念。我们评估了新兴的干细胞模型，它们表现出双潜能，但失去了自主启动和维持发展成完整生物体所必需的顺序命运决定的能力。与保留在正确时间和细胞数量启动命运决定所需信息的全能胚胎细胞不同，这些干细胞已经失去了这种能力。这种关键发育信息的缺失将全能性与全能性区分开来，双潜能干细胞与后者更接近。通过区分全能性、全能性和多能性，我们的目标是完善术语，增强我们对早期胚胎发育的理解，并解决人类研究中的伦理问题。
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引用次数: 0
Genomic snowflakes: how the uniqueness of DNA folding allows us to smell the chemical universe 基因组雪花：DNA折叠的独特性如何让我们闻到化学宇宙
IF 3.7 2区 生物学 Q2 CELL BIOLOGY
Current Opinion in Genetics & Development
Pub Date : 2025-03-18 DOI: 10.1016/j.gde.2025.102329
Longzhi Tan , X. Sunney Xie , Stavros Lomvardas
Olfactory receptor (OR) gene choice, the stable expression of one out of >2000 OR alleles by olfactory sensory neurons, constitutes a gene regulatory process that is driven by three-dimensional nuclear architecture. Moreover, the differentiation-dependent process that culminates in monogenic and monoallelic OR transcription represents a powerful demonstration of the rich mechanistic insight that single-cell genomics and multiomics can provide toward the understanding of a biological process. At this review, we describe the latest advances in the understanding of OR gene regulation and highlight important standing questions regarding the emerging specificity of ultra-long-range genomic interaction and the contribution of transcription and noncoding RNAs.
嗅觉受体（Olfactory receptor， OR）基因选择是嗅觉感觉神经元在2000个OR等位基因中稳定表达一个的过程，是一个由三维核结构驱动的基因调控过程。此外，以单基因和单等位基因OR转录为高潮的分化依赖过程有力地证明了单细胞基因组学和多组学可以为理解生物过程提供丰富的机制见解。在这篇综述中，我们描述了在理解OR基因调控方面的最新进展，并强调了关于超远程基因组相互作用的新特异性以及转录和非编码rna的贡献的重要问题。
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引用次数: 0
Interplay of transposable elements and ageing: epigenetic regulation and potential epitranscriptomic influence 转座因子与衰老的相互作用：表观遗传调控和潜在的表转录组影响
IF 3.7 2区 生物学 Q2 CELL BIOLOGY
Current Opinion in Genetics & Development
Pub Date : 2025-03-17 DOI: 10.1016/j.gde.2025.102331
Raquel García-Vílchez, Diana Guallar
Transposable elements (TEs) are mobile elements, which have been crucial for mammalian genome evolution and function. Their activity, which influences genomic stability, gene expression and chromatin state, is tightly regulated by complex mechanisms. This review examines recent findings on TE regulation and the dynamics and connection during the ageing process. Here, we explore the interplay between chromatin state, DNA, RNA, and histone modifications in controlling TE activity, with a special emphasis in elucidating the emerging role of epitranscriptomic modifications in TE regulation. Additionally, we analyse the connection between TE activation and ageing, with the perspective for future research that could reveal novel targets for alleviating physiological and pathological ageing and age-related diseases.
转座因子（te）是一种可移动因子，在哺乳动物基因组进化和功能中起着至关重要的作用。它们的活性受到复杂机制的严格调控，影响着基因组的稳定性、基因表达和染色质状态。这篇综述探讨了TE调控和衰老过程中动态和联系的最新发现。在这里，我们探讨了染色质状态、DNA、RNA和组蛋白修饰在控制TE活性中的相互作用，特别强调了表观转录组修饰在TE调控中的新作用。此外，我们分析了TE激活与衰老之间的联系，以期为未来的研究揭示缓解生理和病理衰老以及年龄相关疾病的新靶点。
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引用次数: 0
Modification of the RNA methylome in neurodevelopmental disorders 神经发育障碍中RNA甲基组的修饰
IF 3.7 2区 生物学 Q2 CELL BIOLOGY
Current Opinion in Genetics & Development
Pub Date : 2025-03-12 DOI: 10.1016/j.gde.2025.102330
Adriana PerezGrovas-Saltijeral, Joseph Stones, Oliver C Orji, Hala Shaker, Helen M Knight
RNA metabolism is fundamental to protein synthesis, degradation and transport of molecules. Methylation of RNA influences the processing of mRNA, noncoding RNA, tRNA and rRNA. Here, we review accumulating evidence that disruption to the RNA methylome impairs developmental processes and causes neurodevelopmental conditions. We first describe mutated RNA methylation effector protein genes that give rise to neurodevelopmental syndromes. We consider the biological processes thereby disrupted, including translational dynamics at cytoplasmic and mt-ribosomes, synaptic function, energy production and cellular stress. Finally, we discuss novel forms of methylated RNA, such as R-loops and circular RNAs, which may contribute to disease processes. These findings herald an exciting new era to brain research and highlight the significant potential of manipulating the RNA methylome as a therapeutic target in the treatment of neurodevelopmental disorders.
RNA代谢是蛋白质合成、降解和分子运输的基础。RNA的甲基化影响mRNA、非编码RNA、tRNA和rRNA的加工。在这里，我们回顾了越来越多的证据表明，RNA甲基组的破坏会损害发育过程并导致神经发育疾病。我们首先描述突变的RNA甲基化效应蛋白基因引起神经发育综合征。我们认为生物过程因此中断，包括细胞质和mt核糖体的翻译动力学，突触功能，能量产生和细胞应激。最后，我们讨论了新形式的甲基化RNA，如r -环和环状RNA，它们可能有助于疾病过程。这些发现预示着大脑研究的一个令人兴奋的新时代，并突出了操纵RNA甲基组作为治疗神经发育障碍的治疗靶点的巨大潜力。
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引用次数: 0
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