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Alternative splicing of a chromatin modifier alters the transcriptional regulatory programs of stem cell maintenance and neuronal differentiation 染色质修饰因子的交替剪接改变了干细胞维持和神经元分化的转录调控程序
IF 23.9 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-05-02 DOI: 10.1016/j.stem.2024.04.001
Mohammad Nazim, Chia-Ho Lin, An-Chieh Feng, Wen Xiao, Kyu-Hyeon Yeom, Mulin Li, Allison E. Daly, Xianglong Tan, Ha Vu, Jason Ernst, Michael F. Carey, Stephen T. Smale, Douglas L. Black

Development of embryonic stem cells (ESCs) into neurons requires intricate regulation of transcription, splicing, and translation, but how these processes interconnect is not understood. We found that polypyrimidine tract binding protein 1 (PTBP1) controls splicing of DPF2, a subunit of BRG1/BRM-associated factor (BAF) chromatin remodeling complexes. Dpf2 exon 7 splicing is inhibited by PTBP1 to produce the DPF2-S isoform early in development. During neuronal differentiation, loss of PTBP1 allows exon 7 inclusion and DPF2-L expression. Different cellular phenotypes and gene expression programs were induced by these alternative DPF2 isoforms. We identified chromatin binding sites enriched for each DPF2 isoform, as well as sites bound by both. In ESC, DPF2-S preferential sites were bound by pluripotency factors. In neuronal progenitors, DPF2-S sites were bound by nuclear factor I (NFI), while DPF2-L sites were bound by CCCTC-binding factor (CTCF). DPF2-S sites exhibited enhancer modifications, while DPF2-L sites showed promoter modifications. Thus, alternative splicing redirects BAF complex targeting to impact chromatin organization during neuronal development.

胚胎干细胞(ESC)发育成神经元需要转录、剪接和翻译的复杂调控,但这些过程如何相互关联尚不清楚。我们发现多嘧啶束结合蛋白1(PTBP1)控制着DPF2的剪接,DPF2是BRG1/BRM相关因子(BAF)染色质重塑复合物的一个亚基。在发育早期,Dpf2 第 7 外显子的剪接会受到 PTBP1 的抑制,从而产生 DPF2-S 异构体。在神经元分化过程中,PTBP1 的缺失会导致外显子 7 的包含和 DPF2-L 的表达。这些DPF2异构体诱导了不同的细胞表型和基因表达程序。我们确定了富含每种 DPF2 异构体的染色质结合位点,以及两种 DPF2 异构体都结合的位点。在 ESC 中,DPF2-S 优先结合的位点被多能因子结合。在神经祖细胞中,DPF2-S位点与核因子I(NFI)结合,而DPF2-L位点与CCCTC结合因子(CTCF)结合。DPF2-S 位点表现出增强子修饰,而 DPF2-L 位点表现出启动子修饰。因此,在神经元发育过程中,替代剪接会重新定向 BAF 复合物靶向,从而影响染色质组织。
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引用次数: 0
Microbial metabolite steers intestinal stem cell fate under stress 微生物代谢物引导压力下的肠干细胞命运
IF 23.9 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-05-02 DOI: 10.1016/j.stem.2024.04.006
Shu Zhu, Wen Pan

Recently in Cell Metabolism, Wei et al.1 unveiled a brain-to-gut pathway that conveys psychological stress to intestinal epithelial cells, leading to their dysfunction. This gut-brain axis involves a microbial metabolite, indole-3-acetate (IAA), as a niche signal that hampers mitochondrial respiration to skew intestinal stem cell (ISC) fate.

最近,Wei 等人1 在《细胞新陈代谢》(Cell Metabolism)杂志上揭示了一条从大脑到肠道的通路,这条通路将心理压力传递给肠道上皮细胞,导致其功能障碍。这一肠道-大脑轴涉及一种微生物代谢物--吲哚-3-乙酸酯(IAA),它是一种利基信号,阻碍线粒体呼吸,从而改变肠道干细胞(ISC)的命运。
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引用次数: 0
The epidermal circadian clock integrates and subverts brain signals to guarantee skin homeostasis 表皮昼夜节律时钟整合并颠覆大脑信号,保证皮肤平衡
IF 23.9 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-05-02 DOI: 10.1016/j.stem.2024.04.013
Thomas Mortimer, Valentina M. Zinna, Muge Atalay, Carmelo Laudanna, Oleg Deryagin, Guillem Posas, Jacob G. Smith, Elisa García-Lara, Mireia Vaca-Dempere, Leonardo Vinícius Monteiro de Assis, Isabel Heyde, Kevin B. Koronowski, Paul Petrus, Carolina M. Greco, Stephen Forrow, Henrik Oster, Paolo Sassone-Corsi, Patrick-Simon Welz, Pura Muñoz-Cánoves, Salvador Aznar Benitah

In mammals, the circadian clock network drives daily rhythms of tissue-specific homeostasis. To dissect daily inter-tissue communication, we constructed a mouse minimal clock network comprising only two nodes: the peripheral epidermal clock and the central brain clock. By transcriptomic and functional characterization of this isolated connection, we identified a gatekeeping function of the peripheral tissue clock with respect to systemic inputs. The epidermal clock concurrently integrates and subverts brain signals to ensure timely execution of epidermal daily physiology. Timely cell-cycle termination in the epidermal stem cell compartment depends upon incorporation of clock-driven signals originating from the brain. In contrast, the epidermal clock corrects or outcompetes potentially disruptive feeding-related signals to ensure the optimal timing of DNA replication. Together, we present an approach for cataloging the systemic dependencies of daily temporal organization in a tissue and identify an essential gate-keeping function of peripheral circadian clocks that guarantees tissue homeostasis.

在哺乳动物中,昼夜节律时钟网络驱动着组织特异性平衡的日节律。为了剖析组织间的日常交流,我们构建了一个仅由两个节点组成的小鼠最小时钟网络:外周表皮时钟和中枢大脑时钟。通过对这一孤立连接进行转录组学和功能表征,我们确定了外周组织时钟对系统输入的把关功能。表皮时钟同时整合和颠覆大脑信号,以确保表皮日常生理活动的及时执行。表皮干细胞区的细胞周期能否及时终止,取决于是否结合了来自大脑的时钟驱动信号。与此相反,表皮时钟纠正或超越潜在的破坏性进食相关信号,以确保DNA复制的最佳时机。综上所述,我们提出了一种方法,用于对组织中每日时间组织的系统依赖性进行编目,并确定了外周昼夜节律钟保证组织稳态的重要守门功能。
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引用次数: 0
Hallmarks of cancer stemness 癌症干细胞的特征
IF 23.9 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-05-02 DOI: 10.1016/j.stem.2024.04.004
Jia-Jian Loh, Stephanie Ma

Cancer stemness is recognized as a key component of tumor development. Previously coined “cancer stem cells” (CSCs) and believed to be a rare population with rigid hierarchical organization, there is good evidence to suggest that these cells exhibit a plastic cellular state influenced by dynamic CSC-niche interplay. This revelation underscores the need to reevaluate the hallmarks of cancer stemness. Herein, we summarize the techniques used to identify and characterize the state of these cells and discuss their defining and emerging hallmarks, along with their enabling and associated features. We also highlight potential future directions in this field of research.

癌症干细胞被认为是肿瘤发展的关键组成部分。癌症干细胞以前被称为 "癌症干细胞"(CSCs),并被认为是一种具有严格分层组织的稀有群体。这一启示强调了重新评估癌症干性特征的必要性。在此,我们总结了用于识别和描述这些细胞状态的技术,并讨论了它们的决定性特征和新出现的特征,以及它们的赋能特征和相关特征。我们还强调了这一研究领域未来的潜在方向。
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引用次数: 0
Actin pushes open a leaky lumen 肌动蛋白推开泄漏的管腔
IF 23.9 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-05-02 DOI: 10.1016/j.stem.2024.04.003
Jia Guo, Yue Shao

Using a human stem cell-based model to understand how the human epiblast forms at the very beginning of implantation, Indana et al.1 establish a role for pushing forces that are generated by apical actin polymerization and reveal a two-stage, biomechanics-driven lumen growth process underlying epiblast cavity morphogenesis.

Indana 等人1 利用基于人类干细胞的模型来了解人类上胚层在植入初期是如何形成的,他们确定了由顶端肌动蛋白聚合产生的推力的作用,并揭示了上胚层空腔形态发生所依赖的两阶段生物力学驱动的腔体生长过程。
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引用次数: 0
Sox9-coordinated cellular neighborhoods generate fibrosis Sox9 协调的细胞邻域产生纤维化
IF 23.9 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-05-02 DOI: 10.1016/j.stem.2024.04.009
Darrian Bugg, Jennifer Davis

Poorly regenerative organs deposit scar tissue to mend damage. Aggarwal et al. establish that transient Sox9 activity is necessary for early proximal tubule epithelial regeneration, while Trogisch et al. and Aggarwal et al. show that persistent Sox9 activity in epithelial and endothelial cells activates fibroblasts creating fibrotic microdomains in multiple organs.

再生能力差的器官会沉积瘢痕组织以修补损伤。Aggarwal 等人证实,瞬时 Sox9 活性是早期近端小管上皮再生的必要条件,而 Trogisch 等人和 Aggarwal 等人的研究则表明,上皮细胞和内皮细胞中持续的 Sox9 活性会激活成纤维细胞,在多个器官中形成纤维化微域。
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引用次数: 0
Connie Eaves (May 22, 1944–March 7, 2024) 康妮-伊夫(1944 年 5 月 22 日-2024 年 3 月 7 日)
IF 23.9 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-05-02 DOI: 10.1016/j.stem.2024.04.007
Ali Turhan, Franck Nicolini, François Lemoine, Laure Coulombel, Saghi Ghaffari
No Abstract
无摘要
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引用次数: 0
Unveiling the mystery of nuclear RNA homeostasis 揭开核 RNA 平衡的神秘面纱
IF 23.9 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-05-02 DOI: 10.1016/j.stem.2024.03.014
Lin Shan, Ling-Ling Chen

How nuclear RNA homeostasis impacts cellular functions remains elusive. In this issue of Cell Stem Cell, Han et al.1 utilized a controllable protein degradation system targeting EXOSC2 to perturb RNA homeostasis in mouse pluripotent embryonic stem cells, revealing its vital role in orchestrating crucial nuclear events for cellular fitness.

核RNA稳态如何影响细胞功能仍是一个谜。在本期《细胞干细胞》(Cell Stem Cell)杂志上,Han等人1利用一种靶向EXOSC2的可控蛋白降解系统扰乱了小鼠多能胚胎干细胞中的RNA稳态,揭示了它在协调细胞健康的关键核事件中的重要作用。
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引用次数: 0
Remodeling ceramide homeostasis promotes functional maturation of human pluripotent stem cell-derived β cells 重塑神经酰胺平衡促进人类多能干细胞衍生β细胞的功能成熟
IF 23.9 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-05-01 DOI: 10.1016/j.stem.2024.04.010
Huijuan Hua, Yaqi Wang, Xiaofeng Wang, Shusen Wang, Yunlu Zhou, Yinan Liu, Zhen Liang, Huixia Ren, Sufang Lu, Shuangshuang Wu, Yong Jiang, Yue Pu, Xiang Zheng, Chao Tang, Zhongyang Shen, Cheng Li, Yuanyuan Du, Hongkui Deng

Human pluripotent stem cell-derived β cells (hPSC-β cells) show the potential to restore euglycemia. However, the immature functionality of hPSC-β cells has limited their efficacy in application. Here, by deciphering the continuous maturation process of hPSC-β cells post transplantation via single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq), we show that functional maturation of hPSC-β cells is an orderly multistep process during which cells sequentially undergo metabolic adaption, removal of negative regulators of cell function, and establishment of a more specialized transcriptome and epigenome. Importantly, remodeling lipid metabolism, especially downregulating the metabolic activity of ceramides, the central hub of sphingolipid metabolism, is critical for β cell maturation. Limiting intracellular accumulation of ceramides in hPSC-β cells remarkably enhanced their function, as indicated by improvements in insulin processing and glucose-stimulated insulin secretion. In summary, our findings provide insights into the maturation of human pancreatic β cells and highlight the importance of ceramide homeostasis in function acquisition.

人类多能干细胞衍生的β细胞(hPSC-β细胞)具有恢复优生血糖的潜力。然而,hPSC-β细胞的不成熟功能限制了其应用效果。在这里,我们通过单细胞RNA测序(scRNA-seq)和单细胞转座酶可获取染色质测序(scATAC-seq)分析,破解了移植后hPSC-β细胞的持续成熟过程,结果表明,hPSC-β细胞的功能成熟是一个有序的多步骤过程,在这一过程中,细胞依次经历了代谢适应、细胞功能负调控因子的去除以及更特化的转录组和表观基因组的建立。重要的是,重塑脂质代谢,尤其是下调神经酰胺(鞘脂代谢的核心枢纽)的代谢活性,对β细胞的成熟至关重要。限制神经酰胺在 hPSC-β 细胞内的积累可显著增强其功能,这体现在胰岛素处理和葡萄糖刺激的胰岛素分泌的改善上。总之,我们的研究结果为人类胰腺β细胞的成熟提供了见解,并强调了神经酰胺平衡在功能获得中的重要性。
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引用次数: 0
Long-term expandable mouse and human-induced nephron progenitor cells enable kidney organoid maturation and modeling of plasticity and disease 可长期扩增的小鼠和人类诱导肾小球祖细胞实现了肾脏类器官的成熟以及可塑性和疾病模型的建立
IF 23.9 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-04-30 DOI: 10.1016/j.stem.2024.04.002
Biao Huang, Zipeng Zeng, Sunghyun Kim, Connor C. Fausto, Kari Koppitch, Hui Li, Zexu Li, Xi Chen, Jinjin Guo, Chennan C. Zhang, Tianyi Ma, Pedro Medina, Megan E. Schreiber, Mateo W. Xia, Ariel C. Vonk, Tianyuan Xiang, Tadrushi Patel, Yidan Li, Riana K. Parvez, Balint Der, Zhongwei Li

Nephron progenitor cells (NPCs) self-renew and differentiate into nephrons, the functional units of the kidney. Here, manipulation of p38 and YAP activity allowed for long-term clonal expansion of primary mouse and human NPCs and induced NPCs (iNPCs) from human pluripotent stem cells (hPSCs). Molecular analyses demonstrated that cultured iNPCs closely resemble primary human NPCs. iNPCs generated nephron organoids with minimal off-target cell types and enhanced maturation of podocytes relative to published human kidney organoid protocols. Surprisingly, the NPC culture medium uncovered plasticity in human podocyte programs, enabling podocyte reprogramming to an NPC-like state. Scalability and ease of genome editing facilitated genome-wide CRISPR screening in NPC culture, uncovering genes associated with kidney development and disease. Further, NPC-directed modeling of autosomal-dominant polycystic kidney disease (ADPKD) identified a small-molecule inhibitor of cystogenesis. These findings highlight a broad application for the reported iNPC platform in the study of kidney development, disease, plasticity, and regeneration.

肾小球祖细胞(NPC)可自我更新并分化成肾小球,肾小球是肾脏的功能单位。在这里,通过操纵 p38 和 YAP 活性,小鼠和人类原代肾小球原代细胞以及来自人类多能干细胞(hPSCs)的诱导肾小球原代细胞(iNPCs)得以长期克隆扩增。分子分析表明,培养出的 iNPCs 与原代人类 NPCs 非常相似。iNPCs 生成的肾脏器官组织与已公布的人类肾脏器官组织方案相比,具有最小的脱靶细胞类型和更高的荚膜细胞成熟度。令人惊讶的是,NPC 培养基揭示了人类荚膜细胞程序的可塑性,使荚膜细胞重编程为类似 NPC 的状态。基因组编辑的可扩展性和简易性促进了NPC培养中的全基因组CRISPR筛选,发现了与肾脏发育和疾病相关的基因。此外,NPC 引导的常染色体显性多囊肾病(ADPKD)建模还发现了一种小分子囊肿生成抑制剂。这些发现凸显了所报道的 iNPC 平台在肾脏发育、疾病、可塑性和再生研究中的广泛应用。
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Cell stem cell
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