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HIV-specific CD8+ T-cell proliferative response 24 weeks after early antiretroviral therapy initiation is associated with the subsequent reduction in the viral reservoir. 早期抗逆转录病毒治疗开始后24周的hiv特异性CD8+ t细胞增殖反应与随后病毒库的减少有关。
IF 6.4 1区 生物学 Q1 BIOLOGY Pub Date : 2026-01-23 DOI: 10.7554/eLife.106402
Pien Margien van Paassen, Alexander O Pasternak, Dita C Bolluyt, Karel A van Dort, Ad C van Nuenen, Irma Maurer, Brigitte Boeser-Nunnink, Ninée V E J Buchholtz, Tokameh Mahmoudi, Cynthia Lungu, Reinout van Crevel, Casper Rokx, Jori Symons, Monique Nijhuis, Annelou L I P van der Veen, Liffert Vogt, Michelle J Klouwens, Jan M Prins, Neeltje A Kootstra, Godelieve J de Bree

Antiretroviral therapy (ART) initiated in the acute phase of HIV infection (AHI) results in a smaller viral reservoir. However, the impact of early HIV-specific T-cell responses on long-term reservoir dynamics is less well characterized. Therefore, we measured the size of the viral reservoir and functionality of HIV-specific CD8+ T-cell responses after the acute phase at 24 and 156 weeks after ART initiation in people with HIV who started treatment during AHI. A significant reduction in total and defective HIV DNA and a trend toward a reduction in intact HIV DNA were observed between 24 and 156 weeks. Functional CD8+ T-cell responses against HIV peptides Env, Gag, Nef, and Pol were maintained over 3 years after treatment initiation. The proliferative capacity of HIV-specific CD8+ T-cells at 24 weeks of ART was predictive of the degree of reduction in total and defective HIV DNA between 24 and 156 weeks, suggesting HIV-specific CD8+ T-cells may at least partially drive the decline of the viral reservoir. Therefore, enforcing HIV-specific immune responses as early as possible after diagnosis of AHI should be a central focus of HIV cure strategies.

在HIV感染(AHI)的急性期开始抗逆转录病毒治疗(ART)导致更小的病毒库。然而,早期hiv特异性t细胞反应对长期蓄水池动力学的影响尚不清楚。因此,我们测量了病毒库的大小和艾滋病毒特异性CD8+ t细胞反应的功能,在急性期,在开始抗逆转录病毒治疗后24周和156周,在AHI期间开始治疗的艾滋病毒感染者中。在24周至156周期间,观察到总HIV DNA和缺陷HIV DNA的显著减少以及完整HIV DNA减少的趋势。CD8+ t细胞对HIV多肽Env、Gag、Nef和Pol的功能反应在治疗开始后维持3年以上。抗逆转录病毒治疗24周时,HIV特异性CD8+ t细胞的增殖能力可预测24周至156周期间总HIV DNA和缺陷HIV DNA的减少程度,这表明HIV特异性CD8+ t细胞可能至少部分驱动病毒库的下降。因此,在诊断出AHI后尽早实施HIV特异性免疫反应应该是HIV治愈策略的中心重点。
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引用次数: 0
Feedback of peripheral saccade targets to early foveal cortex. 外周扫视目标向早期中央凹皮层反馈。
IF 6.4 1区 生物学 Q1 BIOLOGY Pub Date : 2026-01-22 DOI: 10.7554/eLife.107053
Luca Kämmer, Lisa M Kroell, Tomas Knapen, Martin Rolfs, Martin N Hebart

Human vision is characterized by frequent eye movements and constant shifts in visual input, yet our perception of the world remains remarkably stable. Here, we directly demonstrate image-specific foveal feedback to primary visual cortex in the context of saccadic eye movements. To this end, we used a gaze-contingent fMRI paradigm, in which peripheral saccade targets disappeared before they could be fixated. Despite no direct foveal stimulation, we were able to decode peripheral saccade targets from foveal retinotopic areas, demonstrating that image-specific feedback during saccade preparation may underlie this effect. Decoding was sensitive to shape but not semantic category of natural images, indicating feedback of only low-to-mid-level information. Cross-decoding to a control condition with foveal stimulus presentation indicates a shared representational format between foveal feedback and direct stimulation. Moreover, eccentricity-dependent analyses showed a U-shaped decoding curve, confirming that these results are not explained by spillover of peripheral activity or large receptive fields. Finally, fluctuations in foveal decodability covaried with activity in the intraparietal sulcus, thus providing a candidate region for driving foveal feedback. These findings suggest that foveal cortex predicts the features of incoming stimuli through feedback from higher cortical areas, which offers a candidate mechanism underlying stable perception.

人类视觉的特点是频繁的眼球运动和视觉输入的不断变化,但我们对世界的感知仍然非常稳定。在这里,我们直接证明了在跳眼运动的背景下,初级视觉皮层的图像特异性中央凹反馈。为此,我们使用了注视-偶然fMRI范式,其中外周扫视目标在被注视之前就消失了。尽管没有直接的中央凹刺激,但我们能够从中央凹视网膜定位区域解码外周扫视目标,证明在扫视准备过程中的图像特异性反馈可能是这种效果的基础。解码对自然图像的形状敏感,但对语义类别不敏感,表明仅对中低层次信息进行反馈。交叉解码到具有中央凹刺激呈现的控制条件表明中央凹反馈与直接刺激之间具有共同的表征格式。此外,与偏心率相关的分析显示了u型解码曲线,证实了这些结果不能用外周活动溢出或大的接受野来解释。最后,中央凹可解码性的波动与顶叶内沟的活动共同变化,从而提供了驱动中央凹反馈的候选区域。这些发现表明,中央凹皮层通过来自高层皮质区的反馈来预测传入刺激的特征,这为稳定感知提供了一种候选机制。
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引用次数: 0
A titin missense variant drives atrial electrical remodeling and is associated with atrial fibrillation. 一种titin错义变体驱动心房电重构并与心房颤动相关。
IF 6.4 1区 生物学 Q1 BIOLOGY Pub Date : 2026-01-22 DOI: 10.7554/eLife.104719
Mahmud Arif Pavel, Hanna Chen, Michael Hill, Arvind Sridhar, Miles Barney, Jaime DeSantiago, Abhinaya Baskaran, Asia Owais, Shashank Sandu, Faisal A Darbar, Aylin Ornelas Loredo, Bahaa Al-Azzam, Brandon Chalazan, Jalees Rehman, Dawood Darbar

Rare and common genetic variants contribute to the risk of atrial fibrillation (AF). Although ion channels were among the first AF candidate genes identified, rare loss-of-function variants in structural genes, such as TTN, have also been implicated in AF pathogenesis, partly through the development of atrial myopathy; however, the underlying mechanisms are poorly understood. While TTN truncating variants (TTNtvs) have been causally linked to arrhythmia and cardiomyopathy syndromes, the role of missense variants (mvs) remains unclear. We show that rare TTNmvs are associated with worse clinical outcomes in a single-center ethnic minority clinical cohort and uncover a pathogenic mechanism by which the T32756I variant drives AF. Modeling the TTN-T32756I variant using human induced pluripotent stem cell-derived atrial cardiomyocytes (iPSC-aCMs) revealed that the mutant cells display aberrant contractility, increased activity of a cardiac potassium channel (KCNQ1, Kv7.1), and dysregulated calcium homeostasis without compromising the sarcomeric integrity of the atrial cardiomyocytes. We also show that a titin-binding protein, the Four-and-a-Half Lim domains 2 (FHL2), has increased binding with KCNQ1 and its modulatory subunit KCNE1 in the TTN-T32756I-iPSC-aCMs, enhancing the slow delayed rectifier potassium current (Iks). Suppression of FHL2 in mutant iPSC-aCMs normalized the Iks, supporting FHL2 as an Iks modulator. Our findings demonstrate that a single amino acid substitution in titin not only impairs its function but also remodels ion channels, contributing to AF. These findings underscore the importance of high-throughput screening to assess the pathogenicity of TTNmvs and establish a mechanistic connection between titin, potassium ion channels, and sarcomeric proteins, which may represent a novel therapeutic target.

罕见和常见的基因变异有助于心房颤动(AF)的风险。虽然离子通道是最早发现的房颤候选基因之一,但结构基因中罕见的功能缺失变异,如TTN,也与房颤发病有关,部分是通过心房肌病的发展;然而,人们对其潜在机制知之甚少。虽然TTN截断变异(ttntv)与心律失常和心肌病综合征有因果关系,但错义变异(mvs)的作用仍不清楚。我们发现,在单中心少数民族临床队列中,罕见的TTNmvs与较差的临床结果相关,并揭示了T32756I变体驱动AF的致病机制。利用人诱导多能干细胞来源的心房心肌细胞(iPSC-aCMs)对TTN-T32756I变体进行建模发现,突变细胞表现出异常的收缩性,增加了心脏钾通道的活性(KCNQ1, Kv7.1),在不损害心房心肌细胞肌体完整性的情况下,钙稳态失调。我们还发现,在TTN-T32756I-iPSC-aCMs中,一种titin结合蛋白,4 -半Lim结构域2 (FHL2),增加了与KCNQ1及其调节亚基KCNE1的结合,增强了慢延迟整流钾电流(Iks)。突变iPSC-aCMs中FHL2的抑制使Iks正常化,支持FHL2作为Iks调节剂。我们的研究结果表明,titin中单个氨基酸的取代不仅会损害其功能,还会重塑离子通道,从而导致AF。这些发现强调了高通量筛选对评估TTNmvs的致病性的重要性,并建立了titin、钾离子通道和肌肉蛋白之间的机制联系,这可能是一种新的治疗靶点。
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引用次数: 0
The cellular logic of limb regeneration. 肢体再生的细胞逻辑。
IF 6.4 1区 生物学 Q1 BIOLOGY Pub Date : 2026-01-22 DOI: 10.7554/eLife.110316
Matthew Cherubino, Catherine D McCusker

Hierarchical communication between cells with distinct positional memories orchestrates the regeneration of missing limb structures in axolotls.

具有不同位置记忆的细胞之间的层次交流协调了蝾螈缺失肢体结构的再生。
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引用次数: 0
Anti-resonance in developmental signaling regulates cell fate decisions. 发育信号中的反共振调节细胞命运决定。
IF 6.4 1区 生物学 Q1 BIOLOGY Pub Date : 2026-01-21 DOI: 10.7554/eLife.107794
Samuel J Rosen, Olivier Witteveen, Naomi Baxter, Ryan S Lach, Erik Hopkins, Marianne Bauer, Maxwell Z Wilson

Cells process dynamic signaling inputs to regulate fate decisions during development. While oscillations or waves in key developmental pathways, such as Wnt, have been widely observed, the principles governing how cells decode these signals remain unclear. By leveraging optogenetic control of the Wnt signaling pathway in both HEK293T cells and H9 human embryonic stem cells, we systematically map the relationship between signal frequency and downstream pathway activation. We find that cells exhibit a minimal response to Wnt at certain frequencies, a behavior we term anti-resonance. We developed both detailed biochemical and simplified hidden variable models that explain how anti-resonance emerges from the interplay between fast and slow pathway dynamics. Remarkably, we find that frequency directly influences cell fate decisions involved in human gastrulation; signals delivered at anti-resonant frequencies result in dramatically reduced mesoderm differentiation. Our work reveals a previously unknown mechanism of how cells decode dynamic signals and how anti-resonance may filter against spurious activation. These findings establish new insights into how cells decode dynamic signals with implications for tissue engineering, regenerative medicine, and cancer biology.

细胞在发育过程中处理动态信号输入来调节命运决定。虽然在关键的发育通路(如Wnt)中振荡或波动已被广泛观察到,但控制细胞如何解码这些信号的原理仍不清楚。通过利用HEK293T细胞和H9人胚胎干细胞中Wnt信号通路的光遗传学控制,我们系统地绘制了信号频率与下游通路激活之间的关系。我们发现细胞在某些频率下对Wnt表现出最小的反应,我们称之为反共振。我们开发了详细的生化和简化的隐变量模型,解释了反共振如何从快速和慢速途径动力学之间的相互作用中出现。值得注意的是,我们发现频率直接影响人类原肠胚形成过程中的细胞命运决定;以反共振频率传递的信号导致中胚层分化显著降低。我们的工作揭示了一种以前未知的机制,即细胞如何解码动态信号以及抗共振如何过滤虚假激活。这些发现为细胞如何解码动态信号建立了新的见解,对组织工程、再生医学和癌症生物学具有重要意义。
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引用次数: 0
Ω-Loop mutations control dynamics of the active site by modulating the hydrogen-bonding network in PDC-3 β-lactamase. Ω-Loop突变通过调节PDC-3 β-内酰胺酶的氢键网络来控制活性位点的动力学。
IF 6.4 1区 生物学 Q1 BIOLOGY Pub Date : 2026-01-21 DOI: 10.7554/eLife.107688
Shuang Chen, Andrew R Mack, Andrea M Hujer, Christopher R Bethel, Robert A Bonomo, Shozeb Haider

The expression of antibiotic-inactivating enzymes, such as Pseudomonas-derived cephalosporinase-3 (PDC-3), is a major mechanism of intrinsic resistance in bacteria. Using reinforcement learning-driven molecular dynamics simulations and constant pH MD, we investigate how clinically observed mutations in the Ω-loop (at residues V211, G214, E219, and Y221) alter the structure and function of PDC-3. Our findings reveal that these substitutions modulate the dynamic flexibility of the Ω-loop and the R2-loop, reshaping the cavity of the active site. In particular, E219K and Y221A disrupt the tridentate hydrogen bond network around K67, thus lowering its pKa and promoting proton transfer to the catalytic residue S64. Markov state models reveal that E219K achieves enhanced catalysis by adopting stable, long-lived 'active' conformations, whereas Y221A facilitates activity by rapidly toggling between bond-formed and bond-broken states. In addition, substitutions influence key hydrogen bonds that control the opening and closure of the active-site pocket, consequently influencing the overall size. The pocket expands in all nine clinically identified variants, creating additional space to accommodate bulkier R1 and R2 cephalosporin side chains. Taken together, these results provide a mechanistic basis for how single residue substitutions in the Ω-loop affect catalytic activity. Insights into the structural dynamics of the catalytic site advance our understanding of emerging β-lactamase variants and can inform the rational design of novel inhibitors to combat drug-resistant P. aeruginosa.

抗生素失活酶的表达,如假单胞菌衍生的头孢菌素酶-3 (PDC-3),是细菌内在耐药的主要机制。使用强化学习驱动的分子动力学模拟和恒定pH MD,我们研究了临床观察到的Ω-loop(残基V211, G214, E219和Y221)突变如何改变PDC-3的结构和功能。我们的研究结果表明,这些取代调节了Ω-loop和r2环的动态灵活性,重塑了活性位点的空腔。特别是E219K和Y221A破坏了K67周围的三叉氢键网络,从而降低了K67的pKa,促进了质子向催化残基S64的转移。马尔可夫状态模型显示,E219K通过采用稳定、长寿命的“活性”构象实现了增强的催化作用,而Y221A通过在键形成和键断裂状态之间快速切换来促进活性。此外,取代会影响控制活性位点口袋打开和关闭的关键氢键,从而影响整体尺寸。在所有9种临床鉴定的变异中,囊袋都会扩大,从而产生额外的空间来容纳体积较大的R1和R2头孢菌素侧链。综上所述,这些结果为Ω-loop中单残基取代如何影响催化活性提供了机理基础。对催化位点结构动力学的深入了解促进了我们对新出现的β-内酰胺酶变体的理解,并可以为合理设计新型抑制剂来对抗耐药铜绿假单胞菌提供信息。
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引用次数: 0
Shifting the PPARγ conformational ensemble toward a transcriptionally repressive state improves covalent inhibitor efficacy. 将PPARγ构象集合转移到转录抑制状态可提高共价抑制剂的功效。
IF 6.4 1区 生物学 Q1 BIOLOGY Pub Date : 2026-01-21 DOI: 10.7554/eLife.106697
Liudmyla Arifova, Brian S MacTavish, Zane Laughlin, Mithun Nag Karadi Girdhar, Jinsai Shang, Min-Hsuan Li, Xiaoyu Yu, Di Zhu, Theodore M Kamenecka, Douglas J Kojetin

The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) regulates transcription in response to ligand binding at an orthosteric pocket within the ligand-binding domain (LBD). We previously showed that two covalent ligands, T0070907 and GW9662-extensively used as PPARγ inhibitors to assess off-target activity-weaken but do not completely block ligand binding via an allosteric mechanism associated with pharmacological inverse agonism (Shang and Kojetin, 2024). These covalent inhibitors shift the LBD toward a repressive conformation, where the activation function-2 (AF-2) helix 12 occupies the orthosteric pocket, competing with orthosteric ligand binding. Here, we provide additional support for this allosteric mechanism using two covalent inverse agonists, SR33065 and SR36708, which better stabilize the repressive LBD conformation and are more effective inhibitors of-but also do not completely inhibit-ligand cobinding. Furthermore, we show that ligand cobinding can occur with a previously reported PPARγ dual-site covalent inhibitor, SR16832, which appears to weaken ligand binding through a direct mechanism independent of the allosteric mechanism. These findings underscore the complex nature of the PPARγ LBD conformational ensemble and highlight the need to develop alternative methods for designing more effective covalent inhibitors.

核受体过氧化物酶体增殖体激活受体γ (PPARγ)在配体结合域(LBD)内的正位口袋中调节配体结合的转录。我们之前的研究表明,两种共价配体T0070907和gw9662——广泛用作PPARγ抑制剂来评估脱靶活性——通过与药理学逆激动作用相关的变容机制削弱但不能完全阻断配体结合(Shang和Kojetin, 2024)。这些共价抑制剂将LBD转变为抑制性构象,其中激活功能-2 (AF-2)螺旋12占据正位口袋,与正位配体结合竞争。在这里,我们使用两种共价逆激动剂SR33065和SR36708为这种变构机制提供了额外的支持,它们更好地稳定了抑制性LBD构象,并且是更有效的抑制剂-但也不能完全抑制配体共结合。此外,我们发现配体可以与先前报道的PPARγ双位点共价抑制剂SR16832共结合,该抑制剂似乎通过一种独立于变弹性机制的直接机制削弱配体结合。这些发现强调了PPARγ LBD构象集合的复杂性,并强调了开发设计更有效的共价抑制剂的替代方法的必要性。
{"title":"Shifting the PPARγ conformational ensemble toward a transcriptionally repressive state improves covalent inhibitor efficacy.","authors":"Liudmyla Arifova, Brian S MacTavish, Zane Laughlin, Mithun Nag Karadi Girdhar, Jinsai Shang, Min-Hsuan Li, Xiaoyu Yu, Di Zhu, Theodore M Kamenecka, Douglas J Kojetin","doi":"10.7554/eLife.106697","DOIUrl":"10.7554/eLife.106697","url":null,"abstract":"<p><p>The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) regulates transcription in response to ligand binding at an orthosteric pocket within the ligand-binding domain (LBD). We previously showed that two covalent ligands, T0070907 and GW9662-extensively used as PPARγ inhibitors to assess off-target activity-weaken but do not completely block ligand binding via an allosteric mechanism associated with pharmacological inverse agonism (Shang and Kojetin, 2024). These covalent inhibitors shift the LBD toward a repressive conformation, where the activation function-2 (AF-2) helix 12 occupies the orthosteric pocket, competing with orthosteric ligand binding. Here, we provide additional support for this allosteric mechanism using two covalent inverse agonists, SR33065 and SR36708, which better stabilize the repressive LBD conformation and are more effective inhibitors of-but also do not completely inhibit-ligand cobinding. Furthermore, we show that ligand cobinding can occur with a previously reported PPARγ dual-site covalent inhibitor, SR16832, which appears to weaken ligand binding through a direct mechanism independent of the allosteric mechanism. These findings underscore the complex nature of the PPARγ LBD conformational ensemble and highlight the need to develop alternative methods for designing more effective covalent inhibitors.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12823062/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146009030","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Western lifestyle linked to maladaptive trained immunity. 西方的生活方式与训练有素的免疫力失调有关。
IF 6.4 1区 生物学 Q1 BIOLOGY Pub Date : 2026-01-21 DOI: 10.7554/eLife.105835
Aurelia Josephine Merbecks, Christabel Mennicken, Dennis Marinus de Graaf, Kateryna Shkarina, Theresa Wagner, Eicke Latz

Trained immunity (TI) refers to a state of innate immune cells that, after encountering an initial stimulus and undergoing epigenetic reprogramming and metabolic changes, allows them to respond more effectively to a subsequent challenge. TI yields a survival advantage, particularly in a pathogen-rich context. However, maladaptive TI may damage the host by exacerbating inflammatory diseases. Here we review which aspects of Western lifestyle may contribute to maladaptive TI, including a Western diet, periodontitis, chronic psychological stress, and environmental triggers such as air pollution and microplastics. Finally, we consider lifestyle intervention as a way to prevent or reduce the impact of maladaptive TI.

训练免疫(TI)是指先天免疫细胞在遇到初始刺激并经历表观遗传重编程和代谢变化后,能够更有效地应对后续挑战的一种状态。TI具有生存优势,特别是在病原体丰富的环境中。然而,不适应的TI可能会通过加剧炎症性疾病来损害宿主。在这里,我们回顾了西方生活方式的哪些方面可能导致不适应TI,包括西方饮食、牙周炎、慢性心理压力和环境触发因素,如空气污染和微塑料。最后,我们认为生活方式干预是一种预防或减少不适应TI影响的方法。
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引用次数: 0
cxcl18b-defined transitional state-specific nitric oxide drives injury-induced Müller glia cell-cycle re-entry in the zebrafish retina. cxcl18b定义的过渡状态特异性一氧化氮驱动斑马鱼视网膜损伤诱导的神经胶质细胞周期重新进入。
IF 6.4 1区 生物学 Q1 BIOLOGY Pub Date : 2026-01-21 DOI: 10.7554/eLife.106274
Aojun Ye, Shuguang Yu, Meng Du, Dongming Zhou, Jie He, Chang Chen

In lower vertebrates, retinal Müller glia (MG) exhibit a life-long capacity of cell-cycle re-entry to regenerate neurons following the retinal injury. However, the mechanism driving such injury-induced MG cell-cycle re-entry remains incompletely understood. Combining single-cell transcriptomic analysis and in vivo clonal analysis, we identified previously undescribed cxcl18b-defined MG transitional states as essential routes toward MG proliferation following green/red cone (G/R cone) ablation. Inflammation blockage abolished the triggering of these transitional states, which expressed the gene modules shared by cells of the ciliary marginal zone (CMZ), where life-long adult neurogenesis takes place. Functional studies of the redox properties of these transitional states further demonstrated the regulatory role of nitric oxide (NO) produced by Nos2b in injury-induced MG proliferation. Finally, we developed a viral-based strategy to specifically disrupt nos2b in cxcl18b-defined MG transitional states and revealed the effect of transitional state-specific NO signaling. Our findings elucidate the precision redox mechanism underlying injury-induced MG cell-cycle re-entry, providing insights into species-specific mechanisms for vertebrate retina regeneration.

在低等脊椎动物中,视网膜神经胶质细胞(MG)在视网膜损伤后表现出终身的细胞周期再进入再生神经元的能力。然而,驱动这种损伤诱导的MG细胞周期再进入的机制仍然不完全清楚。结合单细胞转录组学分析和体内克隆分析,我们确定了先前描述的cxcl18b定义的MG过渡状态是绿/红锥(G/R锥)消融后MG增殖的重要途径。炎症阻断消除了这些过渡状态的触发,这些过渡状态表达了睫状体边缘区(CMZ)细胞共享的基因模块,在那里发生终身成人神经发生。对这些过渡态氧化还原特性的功能研究进一步证实了Nos2b产生的一氧化氮(NO)在损伤诱导的MG增殖中的调节作用。最后,我们开发了一种基于病毒的策略,在cxcl18b定义的MG过渡状态中特异性破坏nos2b,并揭示了过渡状态特异性NO信号的作用。我们的研究结果阐明了损伤诱导的MG细胞周期再进入的精确氧化还原机制,为脊椎动物视网膜再生的物种特异性机制提供了见解。
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引用次数: 0
ATAD2 mediates chromatin-bound histone chaperone turnover. ATAD2介导染色质结合组蛋白伴侣蛋白的转换。
IF 6.4 1区 生物学 Q1 BIOLOGY Pub Date : 2026-01-20 DOI: 10.7554/eLife.107582
Ariadni Liakopoulou, Fayçal Boussouar, Daniel Perazza, Sophie Barral, Emeline Lambert, Tao Wang, Florent Chuffart, Ekaterina Bourova-Flin, Charlyne Gard, Denis Puthier, Sophie Rousseaux, Christophe Arnoult, André Verdel, Saadi Khochbin

ATAD2, a conserved protein which is predominantly expressed in embryonic stem (ES) cells and spermatogenic cells, emerges as a crucial regulator of chromatin plasticity. Our previous parallel studies conducted in both ES cells and S. pombe highlighted the fundamental role of ATAD2 in facilitating chromatin-bound histone chaperone turnover. Focusing on mouse spermatogenesis, we demonstrate here that ATAD2 regulates the HIRA-dependent localization of H3.3 on the genome and influences H3.3-mediated gene transcription. Moreover, by modulating histone eviction and the assembly of protamines, ATAD2 ensures proper chromatin condensation and genome packaging in mature sperm. Disruption of Atad2 function in mice leads to abnormal genome organization in mature spermatozoa. Together, these findings establish a previously overlooked level of chromatin dynamic regulation, governed by ATAD2-controlled histone chaperones binding to chromatin, which defines the balance between histone deposition and removal.

ATAD2是一种主要在胚胎干细胞和生精细胞中表达的保守蛋白,是染色质可塑性的重要调节因子。我们之前在胚胎干细胞和S. pombe细胞中进行的平行研究强调了ATAD2在促进染色质结合组蛋白伴侣蛋白转换中的基本作用。在小鼠精子发生过程中,我们证明了ATAD2调控hira依赖的H3.3在基因组上的定位,并影响H3.3介导的基因转录。此外,通过调节组蛋白的排出和蛋白蛋白的组装,ATAD2确保成熟精子中适当的染色质凝聚和基因组包装。小鼠中Atad2功能的破坏导致成熟精子基因组组织异常。总之,这些发现建立了一个以前被忽视的染色质动态调节水平,由atad2控制的组蛋白伴侣与染色质结合,它定义了组蛋白沉积和去除之间的平衡。
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引用次数: 0
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