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ILF3 safeguards telomeres from aberrant homologous recombination as a telomeric R-loop reader. ILF3作为端粒r环读取器保护端粒免受异常同源重组。
IF 13.6 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-07-01 DOI: 10.1093/procel/pwad054
Chuanle Wang, Yan Huang, Yue Yang, Ruofei Li, Yingying Li, Hongxin Qiu, Jiali Wu, Guang Shi, Wenbin Ma, Zhou Songyang

Telomeres are specialized structures at the ends of linear chromosomes that protect genome stability. The telomeric repeat-containing RNA (TERRA) that is transcribed from subtelomeric regions can invade into double-stranded DNA regions and form RNA:DNA hybrid-containing structure called R-loop. In tumor cells, R-loop formation is closely linked to gene expression and the alternative lengthening of telomeres (ALT) pathway. Dysregulated R-loops can cause stalled replication forks and telomere instability. However, how R-loops are recognized and regulated, particularly at telomeres, is not well understood. We discovered that ILF3 selectively associates with telomeric R-loops and safeguards telomeres from abnormal homologous recombination. Knocking out ILF3 results in excessive R-loops at telomeres and triggers telomeric DNA damage responses. In addition, ILF3 deficiency disrupts telomere homeostasis and causes abnormalities in the ALT pathway. Using the proximity-dependent biotin identification (BioID) technology, we mapped the ILF3 interactome and discovered that ILF3 could interact with several DNA/RNA helicases, including DHX9. Importantly, ILF3 may aid in the resolution of telomeric R-loops through its interaction with DHX9. Our findings suggest that ILF3 may function as a reader of telomeric R-loops, helping to prevent abnormal homologous recombination and maintain telomere homeostasis.

端粒是线性染色体末端的特殊结构,可以保护基因组的稳定性。从亚端粒区转录的端粒重复序列RNA (TERRA)可侵入双链DNA区,形成RNA:DNA杂合结构,称为R-loop。在肿瘤细胞中,r环的形成与基因表达和端粒选择性延长(ALT)途径密切相关。失调的r环会导致复制分叉停滞和端粒不稳定。然而,r环是如何被识别和调节的,特别是在端粒上,还没有得到很好的理解。我们发现ILF3选择性地与端粒r环结合,并保护端粒免受异常同源重组。敲除ILF3会导致端粒过量的r环,并引发端粒DNA损伤反应(DDR)。此外,ILF3缺乏破坏端粒稳态并导致ALT通路异常。利用邻近依赖生物素鉴定(BioID)技术,我们绘制了ILF3相互作用组,并发现ILF3可以与几种DNA/RNA解旋酶相互作用,包括DHX9。重要的是,ILF3可能通过与DHX9的相互作用来帮助端粒r环的分解。我们的研究结果表明,ILF3可能作为端粒r环的读取器,有助于防止异常同源重组和维持端粒稳态。
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引用次数: 0
Follicle stimulating hormone controls granulosa cell glutamine synthesis to regulate ovulation. 促卵泡激素可控制颗粒细胞谷氨酰胺的合成,从而调节排卵。
IF 13.6 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-07-01 DOI: 10.1093/procel/pwad065
Kai-Hui Zhang, Fei-Fei Zhang, Zhi-Ling Zhang, Ke-Fei Fang, Wen-Xing Sun, Na Kong, Min Wu, Hai-Ou Liu, Yan Liu, Zhi Li, Qing-Qing Cai, Yang Wang, Quan-Wei Wei, Peng-Cheng Lin, Yan Lin, Wei Xu, Cong-Jian Xu, Yi-Yuan Yuan, Shi-Min Zhao

Polycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility. Inadequate understanding of the ovulation drivers hinders PCOS intervention. Herein, we report that follicle stimulating hormone (FSH) controls follicular fluid (FF) glutamine levels to determine ovulation. Murine ovulation starts from FF-exposing granulosa cell (GC) apoptosis. FF glutamine, which decreases in pre-ovulation porcine FF, elevates in PCOS patients FF. High-glutamine chow to elevate FF glutamine inhibits mouse GC apoptosis and induces hormonal, metabolic, and morphologic PCOS traits. Mechanistically, follicle-development-driving FSH promotes GC glutamine synthesis to elevate FF glutamine, which maintain follicle wall integrity by inhibiting GC apoptosis through inactivating ASK1-JNK apoptotic pathway. FSH and glutamine inhibit the rapture of cultured murine follicles. Glutamine removal or ASK1-JNK pathway activation with metformin or AT-101 reversed PCOS traits in PCOS models that are induced with either glutamine or EsR1-KO. These suggest that glutamine, FSH, and ASK1-JNK pathway are targetable to alleviate PCOS.

多囊卵巢综合征(PCOS)是导致无排卵性不孕症的主要原因。对排卵驱动因素的认识不足阻碍了对多囊卵巢综合征的干预。在此,我们报告了卵泡刺激素(FSH)控制卵泡液(FF)谷氨酰胺水平以决定排卵。小鼠排卵始于FF暴露的颗粒细胞(GC)凋亡。排卵前猪卵泡液谷氨酰胺水平降低,而多囊卵巢综合症患者卵泡液谷氨酰胺水平升高。高谷氨酰胺饲料提高FF谷氨酰胺可抑制小鼠GC凋亡,并诱导多囊卵巢综合征的激素、代谢和形态特征。从机理上讲,卵泡发育驱动的前列腺素促进GC谷氨酰胺的合成以提高FF谷氨酰胺,而FF谷氨酰胺通过抑制ASK1-JNK凋亡途径抑制GC凋亡,从而维持卵泡壁的完整性。FSH 和谷氨酰胺可抑制培养小鼠卵泡的凋亡。去除谷氨酰胺或用二甲双胍或AT-101激活ASK1-JNK通路可逆转用谷氨酰胺或EsR1-KO诱导的多囊卵巢综合征模型的多囊卵巢综合征特征。这表明谷氨酰胺、FSH和ASK1-JNK通路可作为缓解多囊卵巢综合症的靶点。
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引用次数: 0
PKM2, the "K+ sink" in the tumor interstitial fluid. PKM2,肿瘤间质中的 "K+汇"。
IF 13.6 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-06-24 DOI: 10.1093/procel/pwae036
Wenjing Na, Wenfeng Zeng, Kai Song, Youwang Wang, Luoyang Wang, Ziran Zhao, Lingtao Jin, Ping Zhu, Wei Liang
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引用次数: 0
CRISPR-based screening pinpoints H2AZ1 as a driver of senescence in human mesenchymal stem cells. 基于 CRISPR 的筛选确定 H2AZ1 是人类间充质干细胞衰老的驱动因素。
IF 21.1 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-06-19 DOI: 10.1093/procel/pwae035
Ming-Heng Li, Xiaoyu Jiang, Yaobin Jing, Kaowen Yan, Shi-Jia Bi, Si Wang, Shuai Ma, Guang-Hui Liu, Weiqi Zhang, Shuhui Sun, Jing Qu
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引用次数: 0
Mutations in the SARS-CoV-2 spike receptor binding domain and their delicate balance between ACE2 affinity and antibody evasion. SARS-CoV-2 穗状受体结合域的突变及其在 ACE2 亲和力和抗体逃避之间的微妙平衡。
IF 21.1 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-05-28 DOI: 10.1093/procel/pwae007
Song Xue, Yuru Han, Fan Wu, Qiao Wang

Intensive selection pressure constrains the evolutionary trajectory of SARS-CoV-2 genomes and results in various novel variants with distinct mutation profiles. Point mutations, particularly those within the receptor binding domain (RBD) of SARS-CoV-2 spike (S) protein, lead to the functional alteration in both receptor engagement and monoclonal antibody (mAb) recognition. Here, we review the data of the RBD point mutations possessed by major SARS-CoV-2 variants and discuss their individual effects on ACE2 affinity and immune evasion. Many single amino acid substitutions within RBD epitopes crucial for the antibody evasion capacity may conversely weaken ACE2 binding affinity. However, this weakened effect could be largely compensated by specific epistatic mutations, such as N501Y, thus maintaining the overall ACE2 affinity for the spike protein of all major variants. The predominant direction of SARS-CoV-2 evolution lies neither in promoting ACE2 affinity nor evading mAb neutralization but in maintaining a delicate balance between these two dimensions. Together, this review interprets how RBD mutations efficiently resist antibody neutralization and meanwhile how the affinity between ACE2 and spike protein is maintained, emphasizing the significance of comprehensive assessment of spike mutations.

密集的选择压力限制了SARS-CoV-2基因组的进化轨迹,并产生了具有不同突变特征的各种新型变体。点突变,尤其是 SARS-CoV-2 棘突(S)蛋白受体结合域(RBD)内的点突变,会导致受体参与和单克隆抗体(mAb)识别功能的改变。在此,我们回顾了 SARS-CoV-2 主要变种所具有的 RBD 点突变数据,并讨论了它们对 ACE2 亲和力和免疫逃避的各自影响。对抗体规避能力至关重要的 RBD 表位中的许多单氨基酸取代可能会反过来削弱 ACE2 的结合亲和力。然而,这种削弱作用在很大程度上可被特定的外显突变(如 N501Y)所补偿,从而保持 ACE2 与所有主要变体的尖峰蛋白的总体亲和力。SARS-CoV-2 演化的主要方向既不是提高 ACE2 亲和力,也不是逃避 mAb 中和,而是在这两个方面保持微妙的平衡。综上所述,本综述解释了 RBD 突变如何有效地抵抗抗体中和,同时也解释了 ACE2 与尖峰蛋白之间的亲和力是如何维持的,强调了全面评估尖峰突变的重要性。
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引用次数: 0
Identification of FOXO1 as a geroprotector in human synovium through single-nucleus transcriptomic profiling. 通过单核转录组分析确定 FOXO1 是人类滑膜中的老年保护因子
IF 13.6 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-05-28 DOI: 10.1093/procel/pwad060
Feifei Liu, Yi Lu, Xuebao Wang, Shuhui Sun, Huize Pan, Min Wang, Zehua Wang, Weiqi Zhang, Shuai Ma, Guoqiang Sun, Qun Chu, Si Wang, Jing Qu, Guang-Hui Liu

The synovium, a thin layer of tissue that is adjacent to the joints and secretes synovial fluid, undergoes changes in aging that contribute to intense shoulder pain and other joint diseases. However, the mechanism underlying human synovial aging remains poorly characterized. Here, we generated a comprehensive transcriptomic profile of synovial cells present in the subacromial synovium from young and aged individuals. By delineating aging-related transcriptomic changes across different cell types and their associated regulatory networks, we identified two subsets of mesenchymal stromal cells (MSCs) in human synovium, which are lining and sublining MSCs, and found that angiogenesis and fibrosis-associated genes were upregulated whereas genes associated with cell adhesion and cartilage development were downregulated in aged MSCs. Moreover, the specific cell-cell communications in aged synovium mirrors that of aging-related inflammation and tissue remodeling, including vascular hyperplasia and tissue fibrosis. In particular, we identified forkhead box O1 (FOXO1) as one of the major regulons for aging differentially expressed genes (DEGs) in synovial MSCs, and validated its downregulation in both lining and sublining MSC populations of the aged synovium. In human FOXO1-depleted MSCs derived from human embryonic stem cells, we recapitulated the senescent phenotype observed in the subacromial synovium of aged donors. These data indicate an important role of FOXO1 in the regulation of human synovial aging. Overall, our study improves our understanding of synovial aging during joint degeneration, thereby informing the development of novel intervention strategies aimed at rejuvenating the aged joint.

滑膜是毗邻关节并分泌滑液的一层薄薄的组织,在衰老过程中会发生变化,导致强烈的肩痛和其他关节疾病。然而,人体滑膜衰老的机制仍然鲜为人知。在这里,我们建立了一个全面的滑膜细胞类型档案,这些细胞类型存在于年轻人和老年人的肩峰下滑膜中。通过描述各细胞类型与衰老相关的转录组变化及其相关调控网络,我们确定了人体滑膜中间充质基质细胞(MSC)的两个亚群,即内层间充质基质细胞和下层间充质基质细胞,并发现血管生成和纤维化相关基因在衰老过程中上调,而细胞粘附和软骨发育相关基因在衰老过程中下调。此外,衰老滑膜中特定的细胞-细胞通讯反映了与衰老相关的炎症和组织重塑,包括血管增生和组织纤维化。我们特别确定了叉头框 O1(FOXO1)是滑膜间充质干细胞衰老 DEGs 的主要调控因子之一,并验证了其在衰老滑膜的内膜和下层间充质干细胞群中的下调作用。在来源于人类胚胎干细胞的人类 FOXO1 缺失间充质干细胞中,我们重现了在老年供体的肩峰下滑膜中观察到的衰老表型。这些数据表明,FOXO1在调控人体滑膜衰老中发挥着重要作用。总之,我们的研究增进了我们对关节退化过程中滑膜衰老的了解,从而为开发旨在使衰老关节恢复活力的新疗法提供了信息。
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引用次数: 0
Single transmembrane GPCR modulating proteins: neither single nor simple. 单跨膜 GPCR 调节蛋白:既不单一也不简单。
IF 21.1 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-05-28 DOI: 10.1093/procel/pwad035
Meng Wang, Jianjun Lyu, Chao Zhang
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引用次数: 0
Microbiota enterotoxigenic Bacteroides fragilis-secreted BFT-1 promotes breast cancer cell stemness and chemoresistance through its functional receptor NOD1. 微生物群肠毒性脆弱拟杆菌分泌的 BFT-1 通过其功能受体 NOD1 促进乳腺癌细胞的干性和化疗抗性。
IF 13.6 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-05-28 DOI: 10.1093/procel/pwae005
Wei Ma, Lu Zhang, Weilong Chen, Zhaoxia Chang, Juchuanli Tu, Yuanyuan Qin, Yuwen Yao, Mengxue Dong, Jiajun Ding, Siqin Li, Fengkai Li, Qiaodan Deng, Yifei Yang, Tingting Feng, Fanrong Zhang, Xiying Shao, Xueyan He, Lixing Zhang, Guohong Hu, Quentin Liu, Yi-Zhou Jiang, Shu Zhu, Zhi Xiao, Dan Su, Tong Liu, Suling Liu

Tumor-resident microbiota in breast cancer promotes cancer initiation and malignant progression. However, targeting microbiota to improve the effects of breast cancer therapy has not been investigated in detail. Here, we evaluated the microbiota composition of breast tumors and found that enterotoxigenic Bacteroides fragilis (ETBF) was highly enriched in the tumors of patients who did not respond to taxane-based neoadjuvant chemotherapy. ETBF, albeit at low biomass, secreted the toxic protein BFT-1 to promote breast cancer cell stemness and chemoresistance. Mechanistic studies showed that BFT-1 directly bound to NOD1 and stabilized NOD1 protein. NOD1 was highly expressed on ALDH+ breast cancer stem cells (BCSCs) and cooperated with GAK to phosphorylate NUMB and promote its lysosomal degradation, thereby activating the NOTCH1-HEY1 signaling pathway to increase BCSCs. NOD1 inhibition and ETBF clearance increase the chemosensitivity of breast cancer by impairing BCSCs.

乳腺癌中的肿瘤驻留微生物群会促进癌症的发生和恶性发展。然而,针对微生物群来改善乳腺癌治疗效果的研究还不详细。在这里,我们评估了乳腺肿瘤的微生物群组成,发现肠毒性脆弱拟杆菌(ETBF)高度富集于对以紫杉类药物为基础的新辅助化疗无反应的患者的肿瘤中。尽管ETBF的生物量较低,但它能分泌毒性蛋白BFT-1,促进乳腺癌细胞的干性和化疗耐药性。机理研究表明,BFT-1直接与NOD1结合并稳定NOD1蛋白。NOD1在ALDH+乳腺癌干细胞(BCSCs)上高表达,并与GAK合作磷酸化NUMB,促进其溶酶体降解,从而激活NOTCH1-HEY1信号通路,增加BCSCs。抑制 NOD1 和清除 ETBF 可通过损害 BCSCs 增加乳腺癌的化疗敏感性。
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引用次数: 0
Immune rebalancing at the maternal-fetal interface of maternal SARS-CoV-2 infection during early pregnancy. 孕早期母体感染 SARS-CoV-2 后母胎界面的免疫再平衡。
IF 21.1 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-05-28 DOI: 10.1093/procel/pwae006
Chenxiang Xi, Zihui Yan, Dandan Bai, Yalin Zhang, Beiying Wang, Xiaoxiao Han, Li Wu, Xiaohui Shi, Zhiyi Hu, Ming Tang, Zhongqu Su, Yingdong Liu, Binya Liu, Jiqing Yin, Hong Wang, Xiaocui Li, Yanping Zhang, Shaorong Gao, Wenqiang Liu

The current coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2) remains a threat to pregnant women. However, the impact of early pregnancy SARS-CoV-2 infection on the maternal-fetal interface remains poorly understood. Here, we present a comprehensive analysis of single-cell transcriptomics and metabolomics in placental samples infected with SARS-CoV-2 during early pregnancy. Compared to control placentas, SARS-CoV-2 infection elicited immune responses at the maternal-fetal interface and induced metabolic alterations in amino acid and phospholipid profiles during the initial weeks post-infection. However, subsequent immune cell activation and heightened immune tolerance in trophoblast cells established a novel dynamic equilibrium that mitigated the impact on the maternal-fetal interface. Notably, the immune response and metabolic alterations at the maternal-fetal interface exhibited a gradual decline during the second trimester. Our study underscores the adaptive immune tolerance mechanisms and establishment of immunological balance during the first two trimesters following maternal SARS-CoV-2 infection.

目前,由严重急性呼吸系统综合征冠状病毒(SARS-CoV-2)引起的2019年冠状病毒病(COVID-19)大流行仍对孕妇构成威胁。然而,人们对妊娠早期 SARS-CoV-2 感染对母胎界面的影响仍然知之甚少。在这里,我们对妊娠早期感染 SARS-CoV-2 的胎盘样本进行了单细胞转录组学和代谢组学的全面分析。与对照胎盘相比,SARS-CoV-2 感染会引起母胎界面的免疫反应,并在感染后最初几周诱发氨基酸和磷脂谱的代谢改变。然而,随后滋养层细胞中免疫细胞的激活和免疫耐受的增强建立了一种新的动态平衡,减轻了对母胎界面的影响。值得注意的是,母胎界面的免疫反应和新陈代谢变化在第二妊娠期表现出逐渐下降的趋势。我们的研究强调了母体感染 SARS-CoV-2 后前两个妊娠期的适应性免疫耐受机制和免疫平衡的建立。
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引用次数: 0
SMAD2/3-SMYD2 and developmental transcription factors cooperate with cell cycle inhibitors to guide tissue formation. SMAD2/3-SMYD2 和发育转录因子与细胞周期抑制剂合作,引导组织形成。
IF 21.1 1区 生物学 Q1 CELL BIOLOGY Pub Date : 2024-05-17 DOI: 10.1093/procel/pwae031
Stefania Militi, Reshma Nibhani, Martin Pook, Siim Pauklin

Tissue formation and organ homeostasis is achieved by precise coordination of proliferation and differentiation of stem cells and progenitors. While deregulation of these processes can result in degenerative disease or cancer, their molecular interplays remain unclear. Here we show that the switch of human pluripotent stem cell (hPSC) self-renewal to differentiation is associated with the induction of distinct cyclin dependent kinase inhibitors (CDKIs). In hPSCs, Activin/Nodal/TGFβ signalling maintains CDKIs in a poised state via SMAD2/3-NANOG-OCT4-EZH2-SNON transcriptional complex. Upon gradual differentiation, CDKIs are induced by successive transcriptional complexes between SMAD2/3-SMYD2 and developmental regulators such as EOMES, thereby lengthening the G1 phase. This, in turn, induces SMAD2/3 transcriptional activity by blocking its linker phosphorylation. Such SMAD2/3-CDKI positive feedback loops drive the exit from pluripotency and stepwise cell fate specification that could be harnessed for producing cells for therapeutic applications. Our study uncovers fundamental mechanisms how cell fate specification is interconnected to cell cycle dynamics and provides insight to autonomous circuitries governing tissue self-formation.

组织的形成和器官的稳态是通过干细胞和祖细胞增殖和分化的精确协调来实现的。虽然这些过程的失调可导致退行性疾病或癌症,但它们之间的分子相互作用仍不清楚。在这里,我们展示了人类多能干细胞(hPSC)自我更新到分化的转换与不同的细胞周期蛋白依赖性激酶抑制剂(CDKIs)的诱导有关。在hPSC中,Activin/Nodal/TGFβ信号通过SMAD2/3-NANOG-OCT4-EZH2-SNON转录复合物将CDKIs维持在静止状态。在逐渐分化的过程中,CDKIs 会受到 SMAD2/3-SMYD2 和 EOMES 等发育调节因子之间连续转录复合物的诱导,从而延长 G1 阶段。反过来,这又会通过阻断 SMAD2/3 连接器的磷酸化来诱导 SMAD2/3 的转录活性。这种SMAD2/3-CDKI正反馈环路驱动着多能性的退出和细胞命运的逐步分化,可用于生产治疗用细胞。我们的研究揭示了细胞命运规范如何与细胞周期动力学相互关联的基本机制,并为管理组织自我形成的自主回路提供了见解。
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引用次数: 0
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