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Regulation of endogenous retroviruses in murine embryonic stem cells and early embryos. 小鼠胚胎干细胞和早期胚胎中内源性逆转录病毒的调控。
IF 5.3 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-01-17 DOI: 10.1093/jmcb/mjad052
Xinyi Lu

Endogenous retroviruses (ERVs) are important components of transposable elements that constitute ∼40% of the mouse genome. ERVs exhibit dynamic expression patterns during early embryonic development and are engaged in numerous biological processes. Therefore, ERV expression must be closely monitored in cells. Most studies have focused on the regulation of ERV expression in mouse embryonic stem cells (ESCs) and during early embryonic development. This review touches on the classification, expression, and functions of ERVs in mouse ESCs and early embryos and mainly discusses ERV modulation strategies from the perspectives of transcription, epigenetic modification, nucleosome/chromatin assembly, and post-transcriptional control.

内源性逆转录病毒(ERV)是转座元件的重要组成部分,占小鼠基因组的 40%。ERV在早期胚胎发育过程中表现出动态表达模式,并参与许多生物过程。因此,必须密切监测ERV在细胞中的表达。大多数研究都集中于小鼠胚胎干细胞(ESC)和早期胚胎发育过程中ERV表达的调控。本综述涉及ERV在小鼠胚胎干细胞和早期胚胎中的分类、表达和功能,主要从转录、表观遗传修饰、核糖体/染色质组装和转录后调控等角度探讨ERV调控策略。
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引用次数: 0
Stability and function of RCL1 are dependent on the interaction with BMS1. RCL1 的稳定性和功能取决于与 BMS1 的相互作用。
IF 5.5 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-01-05 DOI: 10.1093/jmcb/mjad046
Yong Wang, Zhenyu Zhao, Hongyan Yu, Hui Shi, Boxiang Tao, Yinan He, Jun Chen, Jinrong Peng, Meifu Gan, Li Jan Lo

During ribosome biogenesis, the small subunit (SSU) processome is responsible for 40S assembly. The BMS1/RCL1 complex is a core component of the SSU processome that plays an important role in 18S rRNA processing and maturation. Genetic studies using zebrafish mutants indicate that both Bms1-like (Bms1l) and Rcl1 are essential for digestive organ development. In spite of vital functions of this complex, the mutual dependence of these two nucleolar proteins for the stability and function remains elusive. In this study, we identified an RCL1-interacting domain in BMS1, which is conserved in zebrafish and humans. Moreover, both the protein stability and nucleolar entry of RCL1 depend on its interaction with BMS1, otherwise RCL1 degraded through the ubiquitination-proteasome pathway. Functional studies revealed that overexpression of RCL1 in BMS1-knockdown cells can partially rescue the defects in 18S rRNA processing and cell proliferation, and hepatocyte-specific overexpression of Rcl1 can resume zebrafish liver development in the bms1l substitution mutant bms1lsq163/sq163but not in the knockout mutant bms1lzju1/zju1, which is attributed to the nucleolar entry of Rcl1 in the former mutant. Our data demonstrate that BMS1 and RCL1 interaction is essential for not only pre-rRNA processing but also the communication between ribosome biogenesis and cell cycle regulation.

在核糖体生物发生过程中,小亚基(SSU)过程组负责 40S 组装。BMS1/RCL1 复合物是 SSU 过程组的核心成分,在 18S rRNA 处理和成熟过程中发挥着重要作用。利用斑马鱼突变体进行的遗传学研究表明,Bms1-like(Bms1l)和 Rcl1 对消化器官的发育至关重要。尽管该复合体具有重要功能,但这两种核小体蛋白在稳定性和功能上的相互依赖关系仍然难以确定。在这项研究中,我们在 BMS1 中发现了一个与 RCL1 相互作用的结构域,该结构域在斑马鱼和人类中是保守的。此外,RCL1的蛋白稳定性和进入细胞核都依赖于它与BMS1的相互作用,否则RCL1会通过泛素化-蛋白酶体途径降解。功能研究发现,在BMS1敲除的细胞中过表达RCL1可以部分挽救18S rRNA处理和细胞增殖的缺陷,肝细胞特异性过表达Rcl1可以恢复斑马鱼肝脏发育,在bms1l置换突变体bms1lsq163/sq163中可以,但在基因敲除突变体bms1lzju1/zju1中不能,这归因于Rcl1在前一突变体中的核仁进入。我们的数据表明,BMS1 和 RCL1 的相互作用不仅对预 RNA 处理至关重要,而且对核糖体生物发生和细胞周期调控之间的交流也至关重要。
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引用次数: 0
Cholinergic α7 nAChR signaling suppresses SARS-CoV-2 infection and inflammation in lung epithelial cells. 胆碱能α7 nAChR信号抑制SARS-CoV-2感染和肺上皮细胞炎症。
IF 5.5 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-01-05 DOI: 10.1093/jmcb/mjad048
Jing Wen, Jing Sun, Yanhong Tang, Jincun Zhao, Xiao Su
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引用次数: 0
Estrogen receptor α-mediated signaling inhibits type I interferon response to promote breast carcinogenesis. 雌激素受体α介导的信号传导抑制 I 型干扰素反应,从而促进乳腺癌的发生。
IF 5.5 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-01-05 DOI: 10.1093/jmcb/mjad047
Li-Bo Cao, Zi-Lun Ruan, Yu-Lin Yang, Nian-Chao Zhang, Chuan Gao, Cheguo Cai, Jing Zhang, Ming-Ming Hu, Hong-Bing Shu

Estrogen receptor α (ERα) is an important driver and therapeutic target in ∼70% of breast cancers. How ERα drives breast carcinogenesis is not fully understood. In this study, we show that ERα is a negative regulator of type I interferon (IFN) response. Activation of ERα by its natural ligand estradiol inhibits IFN-β-induced transcription of downstream IFN-stimulated genes (ISGs), whereas ERα deficiency or the stimulation with its antagonist fulvestrant has opposite effects. Mechanistically, ERα induces the expression of the histone 2A variant H2A.Z to restrict the engagement of the IFN-stimulated gene factor 3 (ISGF3) complex to the promoters of ISGs and also interacts with STAT2 to disrupt the assembly of the ISGF3 complex. These two events mutually lead to the inhibition of ISG transcription induced by type I IFNs. In a xenograft mouse model, fulvestrant enhances the ability of IFN-β to suppress ERα+ breast tumor growth. Consistently, clinical data analysis reveals that ERα+ breast cancer patients with higher levels of ISGs exhibit higher long-term survival rates. Taken together, our findings suggest that ERα inhibits type I IFN response via two distinct mechanisms to promote breast carcinogenesis.

雌激素受体α(ERα)是70%乳腺癌的重要驱动因素和治疗靶点。ERα如何驱动乳腺癌的发生尚未完全明了。在这项研究中,我们发现ERα是I型干扰素(IFN)反应的负调控因子。ERα的天然配体雌二醇激活ERα会抑制IFN-β诱导的下游IFN刺激基因(ISGs)的转录,而ERα缺乏或用其拮抗剂氟维司群刺激则会产生相反的效果。从机理上讲,ERα会诱导组蛋白2A变体H2A.Z的表达,从而限制IFN刺激基因因子3(ISGF3)复合物与ISGs启动子的接触,同时ERα还会与STAT2相互作用,破坏ISGF3复合物的组装。这两个事件共同导致 I 型 IFN 诱导的 ISG 转录受到抑制。在异种移植小鼠模型中,氟维司群增强了 IFN-β 抑制 ERα+ 乳腺肿瘤生长的能力。同样,临床数据分析显示,ISGs水平较高的ERα+乳腺癌患者的长期生存率也较高。综上所述,我们的研究结果表明,ERα通过两种不同的机制抑制I型IFN反应,从而促进乳腺癌的发生。
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引用次数: 0
The transcriptional activator Klf5 recruits p300-mediated H3K27ac for maintaining trophoblast stem cell pluripotency. 转录激活因子 Klf5 可通过 p300 介导的 H3K27ac 来维持滋养层干细胞的全能性。
IF 5.5 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-01-05 DOI: 10.1093/jmcb/mjad045
Chengli Dou, Linhui Wu, Jingjing Zhang, Hainan He, Tian Xu, Zhisheng Yu, Peng Su, Xia Zhang, Junling Wang, Yi-Liang Miao, Jilong Zhou

The effective proliferation and differentiation of trophoblast stem cells (TSCs) is indispensable for the development of the placenta, which is the key to maintaining normal fetal growth during pregnancy. Kruppel-like factor 5 (Klf5) is implicated in the activation of pluripotency gene expression in embryonic stem cells (ESCs), yet its function in TSCs is poorly understood. Here, we showed that Klf5 knockdown resulted in the downregulation of core TSC-specific genes, consequently causing rapid differentiation of TSCs. Consistently, Klf5-depleted embryos lost the ability to establish TSCs in vitro. At the molecular level, Klf5 preferentially occupied the proximal promoter regions and maintained an open chromatin architecture of key TSC-specific genes. Deprivation of Klf5 impaired the enrichment of p300, a major histone acetyl transferase of H3 lysine 27 acetylation (H3K27ac), and further reduced the occupancy of H3K27ac at promoter regions, leading to decreased transcriptional activity of TSC pluripotency genes. Thus, our findings highlight a novel mechanism of Klf5 in regulating the self-renewal and differentiation of TSCs and provide a reference for understanding placental development and improving pregnancy rates.

滋养层干细胞(TSCs)的有效增殖和分化对胎盘的发育不可或缺,而胎盘是孕期维持胎儿正常生长的关键。Kruppel样因子5(Klf5)与胚胎干细胞(ESC)中多能基因表达的激活有关,但其在TSCs中的功能却鲜为人知。在这里,我们发现Klf5敲除会导致TSC特异性核心基因下调,从而导致TSCs快速分化。同样,去除了Klf5的胚胎失去了在体外建立TSCs的能力。在分子水平上,Klf5优先占据近端启动子区域,并维持关键TSC特异基因的开放染色质结构。剥夺Klf5会影响p300(H3赖氨酸27乙酰化(H3K27ac)的主要组蛋白乙酰转移酶)的富集,并进一步降低H3K27ac在启动子区域的占据率,从而导致TSC多能基因的转录活性降低。因此,我们的研究结果凸显了Klf5调控TSC自我更新和分化的新机制,为了解胎盘发育和提高妊娠率提供了参考。
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引用次数: 0
Transcriptional pausing induced by ionizing radiation enables the acquisition of radioresistance in nasopharyngeal carcinoma. 电离辐射诱导的转录暂停可使鼻咽癌获得放射抗性。
IF 5.5 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-01-05 DOI: 10.1093/jmcb/mjad044
Honglu Liu, Huanyi Fu, Chunhong Yu, Na Zhang, Canhua Huang, Lu Lv, Chunhong Hu, Fang Chen, Zhiqiang Xiao, Zhuohua Zhang, Huasong Lu, Kai Yuan

Lesions on the DNA template can impact transcription via distinct regulatory pathways. Ionizing radiation (IR) as the mainstay modality for many malignancies elicits most of the cytotoxicity by inducing a variety of DNA damages in the genome. How the IR treatment alters the transcription cycle and whether it contributes to the development of radioresistance remain poorly understood. Here, we report an increase in the paused RNA polymerase II (RNAPII), as indicated by the phosphorylation at serine 5 residue of its C-terminal domain, in recurrent nasopharyngeal carcinoma (NPC) patient samples after IR treatment and cultured NPC cells developing IR resistance. Reducing the pool of paused RNAPII by either inhibiting TFIIH-associated CDK7 or stimulating the positive transcription elongation factor b, a CDK9-CycT1 heterodimer, attenuates IR resistance of NPC cells. Interestingly, the poly(ADP-ribosyl)ation of CycT1, which disrupts its phase separation, is elevated in the IR-resistant cells. Mutation of the major poly(ADP-ribosyl)ation sites of CycT1 decreases RNAPII pausing and restores IR sensitivity. Genome-wide chromatin immunoprecipitation followed by sequencing analyses reveal that several genes involved in radiation response and cell cycle control are subject to the regulation imposed by the paused RNAPII. Particularly, we identify the NIMA-related kinase NEK7 under such regulation as a new radioresistance factor, whose downregulation results in the increased chromosome instability, enabling the development of IR resistance. Overall, our results highlight a novel link between the alteration in the transcription cycle and the acquisition of IR resistance, opening up new opportunities to increase the efficacy of radiotherapy and thwart radioresistance in NPC.

DNA 模板上的损伤可通过不同的调控途径影响转录。电离辐射(IR)是治疗许多恶性肿瘤的主要方法,它通过诱导基因组中的各种 DNA 损伤产生大部分细胞毒性。人们对红外治疗如何改变转录周期以及它是否会导致放射抗药性的产生仍然知之甚少。在这里,我们报告了在接受红外线治疗后的复发性鼻咽癌(NPC)患者样本中,暂停的RNA聚合酶II(RNAPII)增加的情况,其C端结构域丝氨酸5残基的磷酸化表明了这一点。通过抑制与 TFIIH 相关的 CDK7 或刺激 CDK9-CycT1 异源二聚体中的正转录延伸因子 b 来减少暂停的 RNAPII 池,可减轻鼻咽癌细胞的红外抗性。有趣的是,在耐红外细胞中,CycT1 的多(ADP-核糖基)硫酸化会破坏其相分离。突变 CycT1 的主要多聚(ADP-核糖基)连接位点可减少 RNAPII 的暂停并恢复对 IR 的敏感性。全基因组染色质免疫沉淀和测序分析表明,一些参与辐射响应和细胞周期控制的基因受到暂停的 RNAPII 的调控。特别是,我们发现受这种调控的 NIMA 相关激酶 NEK7 是一种新的放射抗性因子,它的下调会导致染色体不稳定性增加,从而产生红外抗性。总之,我们的研究结果突显了转录周期的改变与获得红外耐药性之间的新联系,为提高放疗疗效和挫败鼻咽癌的放射耐药性开辟了新的机遇。
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引用次数: 0
ARTC1-mediated VAPB ADP-ribosylation regulates calcium homeostasis. ARTC1 介导的 VAPB ADP-ribosylation 调节钙稳态。
IF 5.5 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-01-05 DOI: 10.1093/jmcb/mjad043
Xueyao Ma, Mengyuan Li, Yi Liu, Xuefang Zhang, Xiaoyun Yang, Yun Wang, Yipeng Li, Jiayue Wang, Xiuhua Liu, Zhenzhen Yan, Xiaochun Yu, Chen Wu

Mono-ADP-ribosylation (MARylation) is a post-translational modification that regulates a variety of biological processes, including DNA damage repair, cell proliferation, metabolism, and stress and immune responses. In mammals, MARylation is mainly catalyzed by ADP-ribosyltransferases (ARTs), which consist of two groups: ART cholera toxin-like (ARTCs) and ART diphtheria toxin-like (ARTDs, also known as PARPs). The human ARTC (hARTC) family is composed of four members: two active mono-ADP-ARTs (hARTC1 and hARTC5) and two enzymatically inactive enzymes (hARTC3 and hARTC4). In this study, we systematically examined the homology, expression, and localization pattern of the hARTC family, with a particular focus on hARTC1. Our results showed that hARTC3 interacted with hARTC1 and promoted the enzymatic activity of hARTC1 by stabilizing hARTC1. We also identified vesicle-associated membrane protein-associated protein B (VAPB) as a new target of hARTC1 and pinpointed Arg50 of VAPB as the ADP-ribosylation site. Furthermore, we demonstrated that knockdown of hARTC1 impaired intracellular calcium homeostasis, highlighting the functional importance of hARTC1-mediated VAPB Arg50 ADP-ribosylation in regulating calcium homeostasis. In summary, our study identified a new target of hARTC1 in the endoplasmic reticulum and suggested that ARTC1 plays a role in regulating calcium signaling.

单ADP-核糖基化(MARylation)是一种翻译后修饰,可调节多种生物过程,包括DNA损伤修复、细胞增殖、新陈代谢以及应激和免疫反应。在哺乳动物中,MARylation 主要由 ADP 核糖转移酶(ARTs)催化,ARTs 包括两类:类霍乱毒素 ART(ARTCs)和类白喉毒素 ART(ARTDs,又称 PARPs)。人类 ARTC(hARTC)家族由四个成员组成:两个活性单 ADP-ART(hARTC1 和 hARTC5)和两个无酶活性的酶(hARTC3 和 hARTC4)。在这项研究中,我们系统地研究了 hARTC 家族的同源性、表达和定位模式,尤其是 hARTC1。结果表明,hARTC3 与 hARTC1 相互作用,并通过稳定 hARTC1 来促进 hARTC1 的酶活性。我们还发现囊泡相关膜蛋白相关蛋白 B(VAPB)是 hARTC1 的一个新靶点,并确定 VAPB 的 Arg50 为 ADP 核糖基化位点。此外,我们还证明了敲除 hARTC1 会损害细胞内的钙稳态,突出了 hARTC1 介导的 VAPB Arg50 ADP 核糖基化在调节钙稳态中的功能重要性。总之,我们的研究发现了 hARTC1 在内质网中的一个新靶点,并提示 ARTC1 在调节钙信号转导中发挥作用。
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引用次数: 0
The bacterial effector SidN/Lpg1083 promotes cell death by targeting Lamin-B2. 细菌效应物 SidN/Lpg1083 通过靶向 Lamin-B2 促进细胞死亡。
IF 5.5 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2023-11-27 DOI: 10.1093/jmcb/mjad036
Jiajia Gao, Wenwen Xu, Feng Tang, Minrui Xu, Qin Zhou, Xingyuan Yang, Nannan Zhang, Jinming Ma, Qi Yang, Xiaofang Chen, Ximing Qin, Honghua Ge

To facilitate survival, replication, and dissemination, the intracellular pathogen Legionella pneumophila relies on its unique type IVB secretion system (T4SS) to deliver over 330 effectors to hijack host cell pathways in a spatiotemporal manner. The effectors and their host targets are largely unexplored due to their low sequence identity to the known proteins and functional redundancy. The T4SS effector SidN (Lpg1083) is secreted into host cells during the late infection period. However, to the best of our knowledge, the molecular characterization of SidN has not been studied. Herein, we identified SidN as a nuclear envelope-localized effector. Its structure adopts a novel fold, and the N-terminal domain is crucial for its specific subcellular localization. Furthermore, we found that SidN is transported by eukaryotic karyopherin Importin-13 into the nucleus, where it attaches to the N-terminal region of Lamin-B2 to interfere with the integrity of the nuclear envelope, causing nuclear membrane disruption and eventually cell death. Our work provides new insights into the structure and function of an L. pneumophila effector protein, and suggests a potential strategy utilized by the pathogen to promote host cell death and then escape from the host for secondary infection.

为了促进生存、复制和传播,细胞内病原体嗜肺军团菌依靠其独特的 IVB 型分泌系统(T4SS)提供 330 多种效应物,以时空方式劫持宿主细胞通路。由于这些效应子及其宿主靶标与已知蛋白质的序列同一性较低,且存在功能冗余,因此它们在很大程度上尚未被研究。T4SS效应子SidN(Lpg1083)在感染后期被分泌到宿主细胞中。然而,据我们所知,SidN 的分子特征尚未得到研究。在此,我们发现 SidN 是一种定位在核膜上的效应物。它的结构采用了一种新的折叠,N-末端结构域对其特异性亚细胞定位至关重要。此外,我们还发现,SidN被真核生物核糖体蛋白Importin-13运输到细胞核中,在那里它附着在Lamin-B2的N端区域,干扰核包膜的完整性,导致核膜破坏,最终导致细胞死亡。我们的研究为了解嗜肺病毒效应蛋白的结构和功能提供了新的视角,并提出了病原体促进宿主细胞死亡,然后逃离宿主进行二次感染的潜在策略。
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引用次数: 0
Biological functions and applications of circRNAs-next generation of RNA-based therapy. circRNA 的生物功能和应用--下一代基于 RNA 的疗法。
IF 5.5 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2023-11-27 DOI: 10.1093/jmcb/mjad031
Meiling Sun, Yun Yang
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引用次数: 1
Targeted gene panel provides advantages over whole-exome sequencing for diagnosing obesity and diabetes mellitus. 在诊断肥胖症和糖尿病方面,靶向基因面板比全外显子组测序更具优势。
IF 5.5 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2023-11-27 DOI: 10.1093/jmcb/mjad040
Hairong Yu, Haoyong Yu, Rong Zhang, Danfeng Peng, Dandan Yan, Yunjuan Gu, Yuqian Bao, Weiping Jia, Hong Zhang, Cheng Hu

A small fraction of patients diagnosed with obesity or diabetes mellitus has an underlying monogenic cause. Here, we constructed a targeted gene panel consisting of 83 genes reported to be causative for monogenic obesity or diabetes. We performed this panel in 481 patients to detect causative variants and compared these results with whole-exome sequencing (WES) data available for 146 of these patients. The coverage of targeted gene panel sequencing was significantly higher than that of WES. The diagnostic yield in patients sequenced by the panel was 32.9% with subsequent WES leading to three additional diagnoses with two novel genes. In total, 178 variants in 83 genes were detected in 146 patients by targeted sequencing. Three of the 178 variants were missed by WES, although the WES-only approach had a similar diagnostic yield. For the 335 samples only receiving targeted sequencing, the diagnostic yield was 32.2%. In conclusion, taking into account the lower costs, shorter turnaround time, and higher quality of data, targeted sequencing is a more effective screening method for monogenic obesity and diabetes compared to WES. Therefore, this approach could be routinely established and used as a first-tier test in clinical practice for specific patients.

一小部分被诊断为肥胖症或糖尿病的患者有潜在的单基因病因。在这里,我们构建了一个靶向基因面板,该面板由 83 个据报道可导致单基因肥胖症或糖尿病的基因组成。我们对 481 例患者进行了该基因组检测,以发现致病变异,并将这些结果与其中 146 例患者的全外显子组测序(WES)数据进行了比较。靶向基因组测序的覆盖率明显高于全外显子组测序。经该基因组测序的患者的诊断率为 32.9%,而随后的 WES 测序又通过两个新基因确诊了三名患者。通过靶向测序,146 名患者共检测到 83 个基因中的 178 个变异。在这 178 个变异中,WES 漏检了 3 个,尽管仅 WES 方法的诊断率相似。仅接受靶向测序的 335 个样本的诊断率为 32.2%。总之,考虑到较低的成本、较短的周转时间和较高的数据质量,与 WES 相比,靶向测序是一种更有效的单基因肥胖症和糖尿病筛查方法。因此,在临床实践中,这种方法可以作为针对特定患者的第一级检测方法常规建立和使用。
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引用次数: 0
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Journal of Molecular Cell Biology
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