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Deciphering normal and cancer stem cell niches by spatial transcriptomics: opportunities and challenges. 通过空间转录组学解读正常和癌症干细胞龛位：机遇与挑战。

IF 7.5 1区生物学 Q1 CELL BIOLOGY

Genes & development

Pub Date : 2025-01-07 DOI: 10.1101/gad.351956.124

Hirak Sarkar, Eunmi Lee, Sereno L Lopez-Darwin, Yibin Kang

Cancer stem cells (CSCs) often exhibit stem-like attributes that depend on an intricate stemness-promoting cellular ecosystem within their niche. The interplay between CSCs and their niche has been implicated in tumor heterogeneity and therapeutic resistance. Normal stem cells (NSCs) and CSCs share stemness features and common microenvironmental components, displaying significant phenotypic and functional plasticity. Investigating these properties across diverse organs during normal development and tumorigenesis is of paramount research interest and translational potential. Advancements in next-generation sequencing (NGS), single-cell transcriptomics, and spatial transcriptomics have ushered in a new era in cancer research, providing high-resolution and comprehensive molecular maps of diseased tissues. Various spatial technologies, with their unique ability to measure the location and molecular profile of a cell within tissue, have enabled studies on intratumoral architecture and cellular cross-talk within the specific niches. Moreover, delineation of spatial patterns for niche-specific properties such as hypoxia, glucose deprivation, and other microenvironmental remodeling are revealed through multilevel spatial sequencing. This tremendous progress in technology has also been paired with the advent of computational tools to mitigate technology-specific bottlenecks. Here we discuss how different spatial technologies are used to identify NSCs and CSCs, as well as their associated niches. Additionally, by exploring related public data sets, we review the current challenges in characterizing such niches, which are often hindered by technological limitations, and the computational solutions used to address them.

癌症干细胞（CSCs）通常表现出类似干细胞的特性，这取决于其生态位内错综复杂的促进干细胞生态系统。CSCs与其生态位之间的相互作用与肿瘤的异质性和抗药性有关。正常干细胞（NSCs）和CSCs具有相同的干性特征和共同的微环境成分，表现出显著的表型和功能可塑性。研究正常发育和肿瘤发生过程中不同器官的这些特性具有重要的研究意义和转化潜力。下一代测序（NGS）、单细胞转录组学和空间转录组学的进步开创了癌症研究的新纪元，为病变组织提供了高分辨率和全面的分子图谱。各种空间技术具有测量组织内细胞位置和分子特征的独特能力，因此可以研究特定龛位内的瘤内结构和细胞交叉对话。此外，通过多层次空间测序技术，还能发现缺氧、葡萄糖剥夺和其他微环境重塑等特定龛位特性的空间模式。在技术取得巨大进步的同时，计算工具的出现也缓解了特定技术的瓶颈。在这里，我们将讨论如何利用不同的空间技术来识别NSCs和CSCs及其相关的龛位。此外，通过对相关公共数据集的探索，我们回顾了目前在描述此类壁龛特征方面所面临的挑战（这些挑战往往受到技术限制的阻碍），以及用于解决这些问题的计算解决方案。

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引用次数: 0

Genes & Development aims for an expansive horizon 基因与发展的目标是一个广阔的视野

IF 10.5 1区生物学 Q1 CELL BIOLOGY

Genes & development

Pub Date : 2025-01-01 DOI: 10.1101/gad.352534.124

Andrew Dillin

Dear Colleagues,

亲爱的同事们,

引用次数: 0

Genes & Development: an evolution 基因与发育：一种进化

IF 10.5 1区生物学 Q1 CELL BIOLOGY

Genes & development

Pub Date : 2025-01-01 DOI: 10.1101/gad.352552.124

John R. Inglis

With this first Genes & Development issue of 2025, it is my great pleasure to welcome new editorial leadership to the journal.

有了这第一个基因；《2025年发展》杂志，我非常高兴地欢迎新的编辑领导班子加入。

引用次数: 0

E3 ligase substrate adaptor SPOP fine-tunes the UPR of pancreatic β cells E3连接酶底物适配器SPOP微调胰腺β细胞的UPR

IF 10.5 1区生物学 Q1 CELL BIOLOGY

Genes & development

Pub Date : 2024-12-30 DOI: 10.1101/gad.352010.124

Alexis U. Oguh, Matthew W. Haemmerle, Sabyasachi Sen, Andrea V. Rozo, Shristi Shrestha, Jean-Philippe Cartailler, Hossein Fazelinia, Hua Ding, Sam Preza, Juxiang Yang, Xiaodun Yang, Lori Sussel, Juan R. Alvarez-Dominguez, Nicolai Doliba, Lynn A. Spruce, Rafael Arrojo e Drigo, Doris A. Stoffers

The Cullin-3 E3 ligase adaptor protein SPOP targets proteins for ubiquitination and proteasomal degradation. We previously established the β-cell transcription factor (TF) and human diabetes gene PDX1 as an SPOP substrate, suggesting a functional role for SPOP in the β cell. Here, we generated a β-cell-specific Spop deletion mouse strain (Spop^βKO) and found that Spop is necessary to prevent aberrant basal insulin secretion and for maintaining glucose-stimulated insulin secretion through impacts on glycolysis and glucose-stimulated calcium flux. Integration of proteomic, TF-regulatory gene network, and biochemical analyses identified XBP1 as a functionally important SPOP substrate in pancreatic β cells. Furthermore, loss of SPOP strengthened the IRE1α–XBP1 axis of unfolded protein response (UPR) signaling. ER stress promoted proteasomal degradation of SPOP, supporting a model whereby SPOP fine-tunes XBP1 activation during the UPR. These results position SPOP as a regulator of β-cell function and proper UPR activation.

Cullin-3 E3连接酶接头蛋白SPOP靶向泛素化和蛋白酶体降解蛋白。我们之前建立了β细胞转录因子（TF）和人糖尿病基因PDX1作为SPOP底物，这表明SPOP在β细胞中具有功能作用。在这里，我们产生了一个β细胞特异性的Spop缺失小鼠品系（Spopβ ko），并发现Spop通过影响糖酵解和葡萄糖刺激的钙通量来防止异常的基础胰岛素分泌和维持葡萄糖刺激的胰岛素分泌是必要的。结合蛋白质组学、tf调控基因网络和生化分析，确定XBP1是胰腺β细胞中功能重要的SPOP底物。此外，SPOP的缺失增强了未折叠蛋白反应（UPR）信号的IRE1α-XBP1轴。内质网应激促进了SPOP的蛋白酶体降解，支持SPOP在UPR期间微调XBP1激活的模型。这些结果表明SPOP是β细胞功能和正常UPR激活的调节剂。

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引用次数: 0

Alternative splicing controls pan-neuronal homeobox gene expression 选择性剪接控制泛神经元同源盒基因表达

IF 10.5 1区生物学 Q1 CELL BIOLOGY

Genes & development

Pub Date : 2024-12-27 DOI: 10.1101/gad.352184.124

Eduardo Leyva-Díaz, Michael Cesar, Karinna Pe, José Ignacio Jordá-Llorens, Jessica Valdivia, Oliver Hobert

The pan-neuronally expressed and phylogenetically conserved CUT homeobox gene ceh-44/CUX orchestrates pan-neuronal gene expression throughout the nervous system of Caenorhabditis elegans. As in many other species, including humans, ceh-44/CUX is encoded by a complex locus that also codes for a Golgi-localized protein, called CASP (Cux1 alternatively spliced product) in humans and CONE-1 (“CASP of nematodes”) in C. elegans. How gene expression from this complex locus is controlled—and, in C. elegans, directed to all cells of the nervous system—has not been investigated. We show here that pan-neuronal expression of CEH-44/CUX is controlled by a pan-neuronal RNA splicing factor, UNC-75, the C. elegans homolog of vertebrate CELF proteins. During embryogenesis, the cone-1&ceh-44 locus exclusively produces the Golgi-localized CONE-1/CASP protein in all tissues, but upon the onset of postmitotic terminal differentiation of neurons, UNC-75/CELF induces the production of the alternative CEH-44/CUX CUT homeobox gene-encoding transcript exclusively in the nervous system. Hence, UNC-75/CELF-mediated alternative splicing not only directs pan-neuronal gene expression but also excludes a phylogenetically deeply conserved golgin from the nervous system, paralleling surprising spatial specificities of another golgin that we describe here as well. Our findings provide novel insights into how all cells in a nervous system acquire pan-neuronal identity features and reveal unanticipated cellular specificities in Golgi apparatus composition.

在整个秀丽隐杆线虫的神经系统中，泛神经元表达和系统发育保守的CUT同源盒基因ceh-44/CUX协调了泛神经元基因的表达。与包括人类在内的许多其他物种一样，ceh-44/CUX由一个复杂位点编码，该位点也编码高尔基定位蛋白，在人类中称为CASP （Cux1选择性剪接产物），在秀丽隐杆线虫中称为CONE-1（线虫的CASP）。这个复杂位点的基因表达是如何被控制的，在秀丽隐杆线虫中，基因是如何被引导到神经系统的所有细胞的，目前还没有研究。我们在这里表明CEH-44/CUX的泛神经元表达是由泛神经元RNA剪接因子UNC-75控制的，UNC-75是秀丽隐杆线虫的同源脊椎动物CELF蛋白。在胚胎发育过程中，所有组织中CONE-1 &；ceh-44位点只产生高尔基定位的CONE-1/CASP蛋白，但在神经元有丝分裂后终末分化开始时，UNC-75/CELF只在神经系统中诱导产生另一种ceh-44 /CUX CUT同源盒基因编码转录物。因此，UNC-75/ celf介导的选择性剪接不仅指导了泛神经元基因的表达，而且还排除了神经系统中一个系统发育上深度保守的高尔金蛋白，这与我们在这里描述的另一个高尔金蛋白令人惊讶的空间特异性相似。我们的发现为神经系统中所有细胞如何获得泛神经元身份特征提供了新的见解，并揭示了高尔基体组成中意想不到的细胞特异性。

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引用次数: 0

NKX2.2 and KLF4 cooperate to regulate α-cell identity NKX2.2和KLF4协同调节α-细胞身份

IF 10.5 1区生物学 Q1 CELL BIOLOGY

Genes & development

Pub Date : 2024-12-20 DOI: 10.1101/gad.352193.124

Elliott P. Brooks, McKenna R. Casey, Kristen L. Wells, Tsung-Yun Liu, Madeline Van Orman, Lori Sussel

Transcription factors (TFs) are indispensable for maintaining cell identity through regulating cell-specific gene expression. Distinct cell identities derived from a common progenitor are frequently perpetuated by shared TFs, yet the mechanisms that enable these TFs to regulate cell-specific targets are poorly characterized. We report that the TF NKX2.2 is critical for the identity of pancreatic islet α cells by directly activating α-cell genes and repressing alternate islet cell fate genes. When compared with the known role of NKX2.2 in islet β cells, we demonstrate that NKX2.2 regulates α-cell genes, facilitated in part by α-cell-specific DNA binding at gene promoters. Furthermore, we have identified the reprogramming factor KLF4 as having enriched expression in α cells, where it co-occupies NKX2.2-bound α-cell promoters, is necessary for NKX2.2 promoter occupancy in α cells, and coregulates many NKX2.2 α-cell transcriptional targets. Overexpression of Klf4 in β cells is sufficient to manipulate chromatin accessibility, increase binding of NKX2.2 at α-cell-specific promoter sites, and alter expression of NKX2.2-regulated cell-specific targets. This study identifies KLF4 as a novel α-cell factor that cooperates with NKX2.2 to regulate α-cell identity.

转录因子通过调控细胞特异性基因的表达来维持细胞的特性。来自共同祖细胞的不同细胞身份经常被共享的tf延续，然而，使这些tf调节细胞特异性靶标的机制尚不清楚。我们报道，TF NKX2.2通过直接激活α细胞基因和抑制替代胰岛细胞命运基因，对胰岛α细胞的身份至关重要。与已知的NKX2.2在胰岛β细胞中的作用相比，我们证明NKX2.2调节α-细胞基因，部分是通过基因启动子上α-细胞特异性DNA结合来促进的。此外，我们发现重编程因子KLF4在α细胞中表达丰富，它共同占据NKX2.2结合的α-细胞启动子，是NKX2.2启动子在α细胞中占据所必需的，并协同调节许多NKX2.2 α-细胞转录靶点。β细胞中Klf4的过表达足以操纵染色质可及性，增加NKX2.2在α-细胞特异性启动子位点的结合，并改变NKX2.2调节的细胞特异性靶点的表达。本研究发现KLF4是一种新的α-细胞因子，与NKX2.2协同调节α-细胞的身份。

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引用次数: 0

Transcriptional regulation of the piRNA pathway by Ovo in animal ovarian germ cells 卵细胞对动物卵巢生殖细胞piRNA通路的转录调控

IF 10.5 1区生物学 Q1 CELL BIOLOGY

Genes & development

Pub Date : 2024-12-20 DOI: 10.1101/gad.352120.124

Azad Alizada, Gregory J. Hannon, Benjamin Czech Nicholson

The gene-regulatory mechanisms controlling the expression of the germline PIWI-interacting RNA (piRNA) pathway components within the gonads of metazoan species remain largely unexplored. In contrast to the male germline piRNA pathway, which in mice is known to be activated by the testis-specific transcription factor A-MYB, the nature of the ovary-specific gene-regulatory network driving the female germline piRNA pathway remains a mystery. Here, using Drosophila as a model, we combined multiple genomics approaches to reveal the transcription factor Ovo as regulator of the germline piRNA pathway in ovarian germ cells. Ectopic expression of Ovo in ovarian somatic cells activates germline piRNA pathway components, including the ping-pong factors Aubergine, Argonaute-3, and Vasa, leading to assembly of perinuclear cellular structures resembling nuage bodies of germ cells. We found that in ovarian somatic cells, transcription of ovo is repressed by l(3)mbt, thus preventing expression of germline piRNA pathway genes in the soma. Cross-species ChIP-seq and motif analyses demonstrate that Ovo is binding to genomic CCGTTA motifs within the promoters of germline piRNA pathway genes, suggesting a regulation by Ovo in ovaries analogous to that of A-MYB in testes. Our results also show consistent engagement of the Ovo transcription factor family at ovarian piRNA clusters across metazoan species, reflecting a deep evolutionary conservation of this regulatory paradigm from insects to humans.

控制生殖系piwi相互作用RNA （piRNA）途径组分在后生动物性腺内表达的基因调控机制在很大程度上仍未被探索。雄性生殖系piRNA通路已知在小鼠中由睾丸特异性转录因子a - myb激活，与之相反，卵巢特异性基因调控网络驱动雌性生殖系piRNA通路的性质仍然是一个谜。本研究以果蝇为模型，结合多种基因组学方法揭示了转录因子Ovo在卵巢生殖细胞中作为种系piRNA通路的调节因子。卵巢体细胞中Ovo的异位表达激活了种系piRNA通路组分，包括乒乓因子Aubergine、Argonaute-3和Vasa，导致核周细胞结构的组装，类似于生殖细胞的幼体。我们发现在卵巢体细胞中，卵细胞的转录受到l(3)mbt的抑制，从而阻止了种系piRNA通路基因在体细胞中的表达。跨物种ChIP-seq和基序分析表明，Ovo与种系piRNA通路基因启动子中的基因组CCGTTA基序结合，表明Ovo在卵巢中的调控类似于a - myb在睾丸中的调控。我们的研究结果还显示，Ovo转录因子家族在各种后生物物种的卵巢piRNA簇中都有一致的参与，反映了从昆虫到人类这种调节范式的深度进化保护。

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引用次数: 0

LINE1 elements at distal junctions of rDNA repeats regulate nucleolar organization in human embryonic stem cells rDNA重复序列远端连接处的LINE1元件调节人胚胎干细胞的核仁组织

IF 10.5 1区生物学 Q1 CELL BIOLOGY

Genes & development

Pub Date : 2024-12-20 DOI: 10.1101/gad.351979.124

Lamisa Ataei, Juan Zhang, Simon Monis, Krystyna Giemza, Kirti Mittal, Joshua Yang, Mayu Shimomura, Brian McStay, Michael D. Wilson, Miguel Ramalho-Santos

The nucleolus is a major subnuclear compartment where ribosomal DNA (rDNA) is transcribed and ribosomes are assembled. In addition, recent studies have shown that the nucleolus is a dynamic organizer of chromatin architecture that modulates developmental gene expression. rDNA gene units are assembled into arrays located in the p-arms of five human acrocentric chromosomes. Distal junctions (DJs) are ∼400 kb sequences adjacent to rDNA arrays that are thought to anchor them at the nucleolus, although the underlying regulatory elements remain unclear. Here we show that DJs display a dynamic chromosome conformation profile in human embryonic stem cells (hESCs). We identified a primate-specific, full-length insertion of the retrotransposon long interspersed nuclear element 1 (LINE1) in a conserved position across all human DJs. This DJ-LINE1 locus interacts with specific regions of the DJ and is upregulated in naïve hESCs. CRISPR-based deletion and interference approaches revealed that DJ-LINE1 contributes to nucleolar positioning of the DJs. Moreover, we found that the expression of DJ-LINE1 is required for maintenance of the structure and transcriptional output of the nucleolus in hESCs. Silencing of DJ-LINE1 leads to loss of self-renewal, disruption of the landscape of chromatin accessibility, and derepression of earlier developmental programs in naïve hESCs. This work uncovers specific LINE1 elements with a fundamental role in nucleolar organization in hESCs and provides new insights into how the nucleolus functions as a key genome-organizing hub.

核核是核糖体DNA （rDNA）转录和核糖体组装的主要亚核区室。此外，最近的研究表明，核仁是染色质结构的动态组织者，调节发育基因的表达。rDNA基因单元被组装成位于5条人类顶心染色体p臂上的阵列。远端连接（dj）是与rDNA阵列相邻的约400kb的序列，被认为将它们锚定在核核上，尽管潜在的调控元件尚不清楚。在这里，我们展示了dj在人类胚胎干细胞（hESCs）中表现出动态的染色体构象。我们在所有人类dj的保守位置发现了一个灵长类特有的、全长插入的反转录转座子long interspersed nuclear element 1 （LINE1）。这个DJ- line1位点与DJ的特定区域相互作用，并在naïve hESCs中上调。基于crispr的缺失和干扰方法显示，DJ-LINE1参与dj的核仁定位。此外，我们发现DJ-LINE1的表达对于维持hESCs核仁的结构和转录输出是必需的。在naïve hESCs中，DJ-LINE1的沉默导致自我更新的丧失、染色质可及性的破坏以及早期发育程序的抑制。这项工作揭示了在hESCs核仁组织中具有基本作用的特定LINE1元件，并为核仁作为关键的基因组组织中心如何发挥作用提供了新的见解。

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引用次数: 0

Metabolic regulation in adult and aging skeletal muscle stem cells 成人和衰老骨骼肌干细胞的代谢调节

IF 10.5 1区生物学 Q1 CELL BIOLOGY

Genes & development

Pub Date : 2024-12-11 DOI: 10.1101/gad.352277.124

Vittorio Sartorelli, Veronica Ciuffoli

Adult stem cells maintain homeostasis and enable regeneration of most tissues. Quiescence, proliferation, and differentiation of stem cells and their progenitors are tightly regulated processes governed by dynamic transcriptional, epigenetic, and metabolic programs. Previously thought to merely reflect a cell's energy state, metabolism is now recognized for its critical regulatory functions, controlling not only energy and biomass production but also the cell's transcriptome and epigenome. In this review, we explore how metabolic pathways, metabolites, and transcriptional and epigenetic regulators are functionally interlinked in adult and aging skeletal muscle stem cells.

成体干细胞维持体内平衡，使大多数组织能够再生。干细胞及其祖细胞的静止、增殖和分化是受动态转录、表观遗传和代谢程序严格调控的过程。以前人们认为代谢仅仅反映细胞的能量状态，现在人们认识到它具有关键的调节功能，不仅控制能量和生物量的产生，还控制细胞的转录组和表观基因组。在这篇综述中，我们探讨了代谢途径、代谢物、转录和表观遗传调控因子在成年和衰老骨骼肌干细胞中的功能相互联系。

引用次数: 0

Forcing the code: tension modulates signaling to drive morphogenesis and malignancy 强制编码：张力调节信号以驱动形态发生和恶性肿瘤

IF 10.5 1区生物学 Q1 CELL BIOLOGY

Genes & development

Pub Date : 2024-12-05 DOI: 10.1101/gad.352110.124

Radhika Narain, Jonathon M. Muncie-Vasic, Valerie M. Weaver

Development and disease are regulated by the interplay between genetics and the signaling pathways stimulated by morphogens, growth factors, and cytokines. Experimental data highlight the importance of mechanical force in regulating embryonic development, tissue morphogenesis, and malignancy. Force not only sculpts tissue movements to drive embryogenesis and morphogenesis but also modifies the context of biochemical signaling and gene expression to regulate cell and tissue fate. Not surprisingly, experiments have demonstrated that perturbations in cell tension drive malignancy and metastasis by altering biochemical signaling and gene expression through modifications in cytoskeletal tension, transmembrane receptor structure and function, and organelle phenotype that enhance cell growth and survival, alter metabolism, and foster cell migration and invasion. At the tissue level, tumor-associated forces disrupt cell–cell adhesions to perturb tissue organization, compromise vascular integrity to induce hypoxia, and interfere with antitumor immunity to foster metastasis and treatment resistance. Exciting new approaches now exist with which to clarify the relationship between mechanotransduction, biochemical signaling, and gene expression in development and disease. Indeed, gaining insight into these interactions is essential to unravel molecular mechanisms that regulate development and clarify the molecular basis of cancer.

发育和疾病是由遗传和由形态因子、生长因子和细胞因子刺激的信号通路之间的相互作用调节的。实验数据强调了机械力在调节胚胎发育、组织形态发生和恶性肿瘤中的重要性。力不仅塑造组织运动来驱动胚胎发生和形态发生，而且还改变生化信号和基因表达的背景来调节细胞和组织的命运。毫不奇怪，实验已经证明，细胞张力的扰动通过改变细胞骨架张力、跨膜受体结构和功能以及细胞器表型来改变生化信号和基因表达，从而促进细胞生长和存活，改变代谢，促进细胞迁移和侵袭，从而驱动恶性肿瘤和转移。在组织水平上，肿瘤相关的力量破坏细胞-细胞粘附，扰乱组织组织，破坏血管完整性，诱导缺氧，干扰抗肿瘤免疫，促进转移和治疗抵抗。令人兴奋的新方法现在存在，以澄清机械转导，生化信号和基因表达在发育和疾病之间的关系。事实上，深入了解这些相互作用对于揭示调节发育的分子机制和阐明癌症的分子基础至关重要。

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