Pub Date : 2024-11-18DOI: 10.1016/j.devcel.2024.10.012
Michael Housset, Dominic Filion, Nelson Cortes, Hojatollah Vali, Craig A. Mandato, Christian Casanova, Michel Cayouette
The coordinated spatial arrangement of organelles within a tissue plane, known as planar cell polarity (PCP), is critical for organ development and function. Gradients of morphogens and their receptors typically set-up PCP, but whether non-molecular cues, akin to phototropism in plants, also play a part remains unknown. Here, we report that basal bodies of newborn photoreceptor cells in the mouse retina are positioned centrally on the apical surface but then move laterally during the first postnatal week, generating cell-intrinsic asymmetry in the retinal plane. After 1 week, when the eyes open, basal bodies of cone cilia, but not rods, become coordinated across the plane to face the center of the retina. We further show that light is essential for cone PCP, triggering a cascade in which cone transducin interacts with the G-protein-signaling modulator protein 2 (GPSM2) to establish PCP. This work identifies a non-canonical PCP pathway initiated by light.
细胞器在组织平面内的协调空间排列，即平面细胞极性（PCP），对于器官的发育和功能至关重要。形态诱导体及其受体的梯度通常会设置平面细胞极性，但非分子线索（类似于植物中的向光性）是否也在其中起作用仍是未知数。在这里，我们报告了小鼠视网膜中新生感光细胞的基底体在顶端表面居中定位，但在出生后第一周内向侧方移动，从而在视网膜平面上产生细胞内在不对称。1 周后，当眼睛睁开时，视锥纤毛的基底体（而不是视杆细胞）会协调地穿过视网膜平面，面向视网膜中心。我们进一步发现，光对视锥纤毛虫的协调性至关重要，它触发了一个级联，在这个级联中，视锥转导蛋白与 G 蛋白信号调节蛋白 2（GPSM2）相互作用，从而建立起协调性。这项研究发现了一条由光启动的非经典 PCP 通路。
{"title":"Identification of a non-canonical planar cell polarity pathway triggered by light in the developing mouse retina","authors":"Michael Housset, Dominic Filion, Nelson Cortes, Hojatollah Vali, Craig A. Mandato, Christian Casanova, Michel Cayouette","doi":"10.1016/j.devcel.2024.10.012","DOIUrl":"https://doi.org/10.1016/j.devcel.2024.10.012","url":null,"abstract":"The coordinated spatial arrangement of organelles within a tissue plane, known as planar cell polarity (PCP), is critical for organ development and function. Gradients of morphogens and their receptors typically set-up PCP, but whether non-molecular cues, akin to phototropism in plants, also play a part remains unknown. Here, we report that basal bodies of newborn photoreceptor cells in the mouse retina are positioned centrally on the apical surface but then move laterally during the first postnatal week, generating cell-intrinsic asymmetry in the retinal plane. After 1 week, when the eyes open, basal bodies of cone cilia, but not rods, become coordinated across the plane to face the center of the retina. We further show that light is essential for cone PCP, triggering a cascade in which cone transducin interacts with the G-protein-signaling modulator protein 2 (GPSM2) to establish PCP. This work identifies a non-canonical PCP pathway initiated by light.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"99 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142665492","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-18DOI: 10.1016/j.devcel.2024.10.020
A. Sophie Brumm, Afshan McCarthy, Claudia Gerri, Todd Fallesen, Laura Woods, Riley McMahon, Athanasios Papathanasiou, Kay Elder, Phil Snell, Leila Christie, Patricia Garcia, Valerie Shaikly, Mohamed Taranissi, Paul Serhal, Rabi A. Odia, Mina Vasilic, Anna Osnato, Peter J. Rugg-Gunn, Ludovic Vallier, Caroline S. Hill, Kathy K. Niakan
The human blastocyst contains the pluripotent epiblast from which human embryonic stem cells (hESCs) can be derived. ACTIVIN/NODAL signaling maintains expression of the transcription factor NANOG and in vitro propagation of hESCs. It is unknown whether this reflects a functional requirement for epiblast development in human embryos. Here, we characterized NODAL signaling activity during pre-implantation human development. We showed that NANOG is an early molecular marker restricted to the nascent human pluripotent epiblast and was initiated prior to the onset of NODAL signaling. We further demonstrated that expression of pluripotency-associated transcription factors NANOG, SOX2, OCT4, and KLF17 were maintained in the epiblast in the absence of NODAL signaling activity. Genome-wide transcriptional analysis showed that NODAL signaling inhibition did not decrease NANOG transcription or impact the wider pluripotency-associated gene regulatory network. These data suggest differences in the signaling requirements regulating pluripotency in the pre-implantation human epiblast compared with existing hESC culture.
{"title":"Initiation and maintenance of the pluripotent epiblast in pre-implantation human development is independent of NODAL signaling","authors":"A. Sophie Brumm, Afshan McCarthy, Claudia Gerri, Todd Fallesen, Laura Woods, Riley McMahon, Athanasios Papathanasiou, Kay Elder, Phil Snell, Leila Christie, Patricia Garcia, Valerie Shaikly, Mohamed Taranissi, Paul Serhal, Rabi A. Odia, Mina Vasilic, Anna Osnato, Peter J. Rugg-Gunn, Ludovic Vallier, Caroline S. Hill, Kathy K. Niakan","doi":"10.1016/j.devcel.2024.10.020","DOIUrl":"https://doi.org/10.1016/j.devcel.2024.10.020","url":null,"abstract":"The human blastocyst contains the pluripotent epiblast from which human embryonic stem cells (hESCs) can be derived. ACTIVIN/NODAL signaling maintains expression of the transcription factor <em>NANOG</em> and <em>in vitro</em> propagation of hESCs. It is unknown whether this reflects a functional requirement for epiblast development in human embryos. Here, we characterized NODAL signaling activity during pre-implantation human development. We showed that NANOG is an early molecular marker restricted to the nascent human pluripotent epiblast and was initiated prior to the onset of NODAL signaling. We further demonstrated that expression of pluripotency-associated transcription factors NANOG, SOX2, OCT4, and KLF17 were maintained in the epiblast in the absence of NODAL signaling activity. Genome-wide transcriptional analysis showed that NODAL signaling inhibition did not decrease <em>NANOG</em> transcription or impact the wider pluripotency-associated gene regulatory network. These data suggest differences in the signaling requirements regulating pluripotency in the pre-implantation human epiblast compared with existing hESC culture.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"76 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142665493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-15DOI: 10.1016/j.devcel.2024.10.019
Yannick Carrier, Laura Quintana Rio, Nadia Formicola, Vicente de Sousa-Xavier, Maha Tabet, Yu-Chieh David Chen, Aicha Haji Ali, Maëva Wislez, Lisa Orts, Alexander Borst, Filipe Pinto-Teixeira
Layer-specific brain computations depend on neurons synapsing with specific partners in distinct laminae. In the Drosophila lobula plate, axons of the four subtypes of T4 and T5 visual motion direction-selective neurons segregate into four layers, where they synapse with distinct subsets of postsynaptic neurons. Here, we identify a layer-specific expression of different receptor-ligand pairs of the Beat and Side families of cell adhesion molecules between T4/T5s and their postsynaptic partners. Developmental genetic analysis demonstrate that Beat/Side-mediated interactions are required to restrict innervation of T4/T5 axons and the dendrites of their partners to a single layer. We show that Beat/Side interactions are not required for synaptogenesis. Instead, they contribute to synaptic specificity by biasing cellular adjacency, causing neurons to segregate in discrete layers, restricting partner availability before synaptogenesis. We propose that the emergence of synaptic specificity relies on a competitive dynamic among postsynaptic partners with shared Beat/Side expression to adhere with T4/T5s.
{"title":"Biased cell adhesion organizes the Drosophila visual motion integration circuit","authors":"Yannick Carrier, Laura Quintana Rio, Nadia Formicola, Vicente de Sousa-Xavier, Maha Tabet, Yu-Chieh David Chen, Aicha Haji Ali, Maëva Wislez, Lisa Orts, Alexander Borst, Filipe Pinto-Teixeira","doi":"10.1016/j.devcel.2024.10.019","DOIUrl":"https://doi.org/10.1016/j.devcel.2024.10.019","url":null,"abstract":"Layer-specific brain computations depend on neurons synapsing with specific partners in distinct laminae. In the <em>Drosophila</em> lobula plate, axons of the four subtypes of T4 and T5 visual motion direction-selective neurons segregate into four layers, where they synapse with distinct subsets of postsynaptic neurons. Here, we identify a layer-specific expression of different receptor-ligand pairs of the Beat and Side families of cell adhesion molecules between T4/T5s and their postsynaptic partners. Developmental genetic analysis demonstrate that Beat/Side-mediated interactions are required to restrict innervation of T4/T5 axons and the dendrites of their partners to a single layer. We show that Beat/Side interactions are not required for synaptogenesis. Instead, they contribute to synaptic specificity by biasing cellular adjacency, causing neurons to segregate in discrete layers, restricting partner availability before synaptogenesis. We propose that the emergence of synaptic specificity relies on a competitive dynamic among postsynaptic partners with shared Beat/Side expression to adhere with T4/T5s.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"1 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142637590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-13DOI: 10.1016/j.devcel.2024.10.016
Olga Korenkova, Shiyu Liu, Inès Prlesi, Anna Pepe, Shahad Albadri, Filippo Del Bene, Chiara Zurzolo
Tunneling nanotubes (TNTs) are thin intercellular connections that facilitate the transport of diverse cargoes, ranging from ions to organelles. While TNT studies have predominantly been conducted in cell cultures, the existence of open-ended TNTs within live organisms remains unverified. Despite the observation of intercellular connections during embryonic development across various species, their functional role in facilitating material transfer between connected cells has not been confirmed. In this study, we performed mosaic labeling of gastrula cells in zebrafish embryos to demonstrate the coexistence of TNT-like structures alongside other cellular protrusions. These embryonic TNT-like connections exhibited a morphology similar to that of TNTs described in cell culture, appeared to have similar formation mechanisms, and could be induced by Eps8 overexpression and CK666 treatment. Most notably, we demonstrated their capability to transfer both soluble cargoes and organelles, thus confirming their open-endedness. This study demonstrates the existence of functional, open-ended TNTs in a living embryo.
{"title":"Tunneling nanotubes enable intercellular transfer in zebrafish embryos","authors":"Olga Korenkova, Shiyu Liu, Inès Prlesi, Anna Pepe, Shahad Albadri, Filippo Del Bene, Chiara Zurzolo","doi":"10.1016/j.devcel.2024.10.016","DOIUrl":"https://doi.org/10.1016/j.devcel.2024.10.016","url":null,"abstract":"Tunneling nanotubes (TNTs) are thin intercellular connections that facilitate the transport of diverse cargoes, ranging from ions to organelles. While TNT studies have predominantly been conducted in cell cultures, the existence of open-ended TNTs within live organisms remains unverified. Despite the observation of intercellular connections during embryonic development across various species, their functional role in facilitating material transfer between connected cells has not been confirmed. In this study, we performed mosaic labeling of gastrula cells in zebrafish embryos to demonstrate the coexistence of TNT-like structures alongside other cellular protrusions. These embryonic TNT-like connections exhibited a morphology similar to that of TNTs described in cell culture, appeared to have similar formation mechanisms, and could be induced by Eps8 overexpression and CK666 treatment. Most notably, we demonstrated their capability to transfer both soluble cargoes and organelles, thus confirming their open-endedness. This study demonstrates the existence of functional, open-ended TNTs in a living embryo.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"8 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-12DOI: 10.1016/j.devcel.2024.10.013
Kira L. Marshall, Daniel J. Stadtmauer, Jamie Maziarz, Günter P. Wagner, Bluma J. Lesch
Mammalian spermatogenesis is a highly stereotyped and conserved developmental process that is essential for fitness. At the same time, gene expression in spermatogenic cells is rapidly evolving. This combination of features has been suggested to drive rapid fixation of new gene expression patterns. Using a high-resolution dataset comprising bulk and single-cell data from juvenile and adult testes of the opossum Monodelphis domestica, a model marsupial, we define the developmental timing of the spermatogenic first wave in opossum and delineate conserved and divergent gene expression programs across the placental-marsupial split by comparison to equivalent data from mouse, a model placental mammal. Epigenomic data confirmed divergent regulation at the level of transcription, and comparison to data from four additional amniote species identified hundreds of genes with evidence of rapid fixation of expression. This gene set encompasses known and previously undescribed regulators of spermatogenic development.
{"title":"Evolutionary innovations in germline biology of placental mammals identified by transcriptomics of first-wave spermatogenesis in opossum","authors":"Kira L. Marshall, Daniel J. Stadtmauer, Jamie Maziarz, Günter P. Wagner, Bluma J. Lesch","doi":"10.1016/j.devcel.2024.10.013","DOIUrl":"https://doi.org/10.1016/j.devcel.2024.10.013","url":null,"abstract":"Mammalian spermatogenesis is a highly stereotyped and conserved developmental process that is essential for fitness. At the same time, gene expression in spermatogenic cells is rapidly evolving. This combination of features has been suggested to drive rapid fixation of new gene expression patterns. Using a high-resolution dataset comprising bulk and single-cell data from juvenile and adult testes of the opossum <em>Monodelphis domestica</em>, a model marsupial, we define the developmental timing of the spermatogenic first wave in opossum and delineate conserved and divergent gene expression programs across the placental-marsupial split by comparison to equivalent data from mouse, a model placental mammal. Epigenomic data confirmed divergent regulation at the level of transcription, and comparison to data from four additional amniote species identified hundreds of genes with evidence of rapid fixation of expression. This gene set encompasses known and previously undescribed regulators of spermatogenic development.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"9 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-12DOI: 10.1016/j.devcel.2024.10.014
Fengquan Li, Jiayu Wang, Pengcheng Wang, Lin Li
Changes in light quality and quantity experienced by many shade-intolerant plants grown in close proximity lead to transcriptional reprogramming and shade avoidance syndrome (SAS). Despite the importance of phosphorylation-dependent signaling in cellular physiology, phosphorylation events during SAS are largely unknown. Here, we examined shade-regulated phosphorylation events in Arabidopsis using quantitative phosphoproteomics. We confirmed shade-induced dephosphorylation of bZIP59, a basic region/leucine zipper motif (bZIP) transcription factor. Shade treatment promotes the nuclear localization of bZIP59, which can be mimicked by mutation of the phosphorylation sites on bZIP59. Phenotypic analysis identified that bZIP59 negatively regulated shade-induced hypocotyl elongation. bZIP59 repressed the shade-induced activation of certain growth-related genes, while shade increased the DNA binding of bZIP59. Furthermore, the protein phosphatase 2A (PP2A) mediated dephosphorylation of bZIP59. Our study characterized a previously unidentified mechanism by which the phytochrome B (phyB)-PP2A-bZIP59 regulatory module integrates shade signals and transcriptomes, broadening our knowledge of phosphorylation strategies for rapid adaptation to shade.
许多近距离生长的不耐阴植物经历的光质和光量的变化会导致转录重编程和避阴综合征（SAS）。尽管磷酸化依赖性信号在细胞生理学中非常重要，但 SAS 期间的磷酸化事件在很大程度上还不为人所知。在这里，我们利用定量磷酸化蛋白质组学研究了拟南芥中受荫调控的磷酸化事件。我们证实了遮荫诱导的 bZIP59（一种基本区/亮氨酸拉链基序（bZIP）转录因子）去磷酸化。遮荫处理可促进 bZIP59 的核定位，而 bZIP59 上的磷酸化位点可通过突变模拟。表型分析发现，bZIP59 对遮荫诱导的下胚轴伸长有负向调节作用。bZIP59 抑制了遮荫诱导的某些生长相关基因的激活，而遮荫则增加了 bZIP59 的 DNA 结合。此外，蛋白磷酸酶 2A（PP2A）介导了 bZIP59 的去磷酸化。我们的研究揭示了植物色素B（phyB）-PP2A-bZIP59调控模块整合遮荫信号和转录组的一种先前未发现的机制，拓宽了我们对快速适应遮荫的磷酸化策略的认识。
{"title":"Dephosphorylation of bZIP59 by PP2A ensures appropriate shade avoidance response in Arabidopsis","authors":"Fengquan Li, Jiayu Wang, Pengcheng Wang, Lin Li","doi":"10.1016/j.devcel.2024.10.014","DOIUrl":"https://doi.org/10.1016/j.devcel.2024.10.014","url":null,"abstract":"Changes in light quality and quantity experienced by many shade-intolerant plants grown in close proximity lead to transcriptional reprogramming and shade avoidance syndrome (SAS). Despite the importance of phosphorylation-dependent signaling in cellular physiology, phosphorylation events during SAS are largely unknown. Here, we examined shade-regulated phosphorylation events in <em>Arabidopsis</em> using quantitative phosphoproteomics. We confirmed shade-induced dephosphorylation of bZIP59, a basic region/leucine zipper motif (bZIP) transcription factor. Shade treatment promotes the nuclear localization of bZIP59, which can be mimicked by mutation of the phosphorylation sites on bZIP59. Phenotypic analysis identified that bZIP59 negatively regulated shade-induced hypocotyl elongation. bZIP59 repressed the shade-induced activation of certain growth-related genes, while shade increased the DNA binding of bZIP59. Furthermore, the protein phosphatase 2A (PP2A) mediated dephosphorylation of bZIP59. Our study characterized a previously unidentified mechanism by which the phytochrome B (phyB)-PP2A-bZIP59 regulatory module integrates shade signals and transcriptomes, broadening our knowledge of phosphorylation strategies for rapid adaptation to shade.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"95 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-11DOI: 10.1016/j.devcel.2024.10.011
Andrew T. Plygawko, Camille Stephan-Otto Attolini, Ioanna Pitsidianaki, David P. Cook, Alistair C. Darby, Kyra Campbell
The Drosophila adult midgut progenitor cells (AMPs) give rise to all cells in the adult midgut epithelium, including the intestinal stem cells (ISCs). While they share many characteristics with the ISCs, it remains unclear how they are generated in the early embryo. Here, we show that they arise from a population of endoderm cells, which exhibit multiple similarities with Drosophila neuroblasts. These cells, which we have termed endoblasts, are patterned by homothorax (Hth) and undergo asymmetric divisions using the same molecular machinery as neuroblasts. We also show that the conservation of this molecular machinery extends to the generation of the enteroendocrine lineages. Parallels have previously been drawn between the pupal ISCs and larval neuroblasts. Our results suggest that these commonalities exist from the earliest stages of specification of progenitor cells of the intestinal and nervous systems and may represent an ancestral pathway for multipotent progenitor cell specification.
{"title":"The Drosophila adult midgut progenitor cells arise from asymmetric divisions of neuroblast-like cells","authors":"Andrew T. Plygawko, Camille Stephan-Otto Attolini, Ioanna Pitsidianaki, David P. Cook, Alistair C. Darby, Kyra Campbell","doi":"10.1016/j.devcel.2024.10.011","DOIUrl":"https://doi.org/10.1016/j.devcel.2024.10.011","url":null,"abstract":"The <em>Drosophila</em> adult midgut progenitor cells (AMPs) give rise to all cells in the adult midgut epithelium, including the intestinal stem cells (ISCs). While they share many characteristics with the ISCs, it remains unclear how they are generated in the early embryo. Here, we show that they arise from a population of endoderm cells, which exhibit multiple similarities with <em>Drosophila</em> neuroblasts. These cells, which we have termed endoblasts, are patterned by homothorax (Hth) and undergo asymmetric divisions using the same molecular machinery as neuroblasts. We also show that the conservation of this molecular machinery extends to the generation of the enteroendocrine lineages. Parallels have previously been drawn between the pupal ISCs and larval neuroblasts. Our results suggest that these commonalities exist from the earliest stages of specification of progenitor cells of the intestinal and nervous systems and may represent an ancestral pathway for multipotent progenitor cell specification.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"4 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-11DOI: 10.1016/j.devcel.2024.10.017
Anastasiia Tonelli, Pascal Cousin, Aleksander Jankowski, Bihan Wang, Julien Dorier, Jonas Barraud, Sanyami Zunjarrao, Maria Cristina Gambetta
Long-range transcriptional activation of gene promoters by abundant enhancers in animal genomes calls for mechanisms to limit inappropriate regulation. DNA elements called insulators serve this purpose by shielding promoters from an enhancer when interposed. Unlike promoters and enhancers, insulators have not been systematically characterized due to lacking high-throughput screening assays, and questions regarding how insulators are distributed and encoded in the genome remain. Here, we establish “insulator-seq” as a plasmid-based massively parallel reporter assay in Drosophila cultured cells to perform a systematic insulator screen of selected genomic loci. Screening developmental gene loci showed that not all insulator protein binding sites effectively block enhancer-promoter communication. Deep insulator mutagenesis identified sequences flexibly positioned around the CTCF insulator protein binding motif that are critical for functionality. The ability to screen millions of DNA sequences without positional effect has enabled functional mapping of insulators and provided further insights into the determinants of insulators.
在动物基因组中，大量增强子对基因启动子进行长程转录激活，这就需要建立机制来限制不适当的调控。被称为 "绝缘子 "的DNA元件就能达到这一目的，它能在启动子与增强子之间起屏蔽作用。与启动子和增强子不同，由于缺乏高通量筛选检测方法，绝缘子还没有得到系统的表征，关于绝缘子如何在基因组中分布和编码的问题依然存在。在这里，我们在果蝇培养细胞中建立了 "绝缘体-序列"（insulator-seq）这种基于质粒的大规模并行报告检测方法，对选定的基因组位点进行系统的绝缘体筛选。对发育基因位点的筛选表明，并非所有绝缘体蛋白结合位点都能有效阻断增强子-启动子通讯。深度绝缘体突变确定了 CTCF 绝缘体蛋白结合基团周围灵活定位的序列，这些序列对功能至关重要。筛选数百万个无位置效应的 DNA 序列的能力使我们能够绘制绝缘体的功能图谱，并进一步深入了解绝缘体的决定因素。
{"title":"Systematic screening of enhancer-blocking insulators in Drosophila identifies their DNA sequence determinants","authors":"Anastasiia Tonelli, Pascal Cousin, Aleksander Jankowski, Bihan Wang, Julien Dorier, Jonas Barraud, Sanyami Zunjarrao, Maria Cristina Gambetta","doi":"10.1016/j.devcel.2024.10.017","DOIUrl":"https://doi.org/10.1016/j.devcel.2024.10.017","url":null,"abstract":"Long-range transcriptional activation of gene promoters by abundant enhancers in animal genomes calls for mechanisms to limit inappropriate regulation. DNA elements called insulators serve this purpose by shielding promoters from an enhancer when interposed. Unlike promoters and enhancers, insulators have not been systematically characterized due to lacking high-throughput screening assays, and questions regarding how insulators are distributed and encoded in the genome remain. Here, we establish “insulator-seq” as a plasmid-based massively parallel reporter assay in <em>Drosophila</em> cultured cells to perform a systematic insulator screen of selected genomic loci. Screening developmental gene loci showed that not all insulator protein binding sites effectively block enhancer-promoter communication. Deep insulator mutagenesis identified sequences flexibly positioned around the CTCF insulator protein binding motif that are critical for functionality. The ability to screen millions of DNA sequences without positional effect has enabled functional mapping of insulators and provided further insights into the determinants of insulators.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"19 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-07DOI: 10.1016/j.devcel.2024.10.009
Katherine Gillis, Walter A. Orellana, Emily Wilson, Timothy J. Parnell, Gabriela Fort, Pengshu Fang, Headtlove Essel Dadzie, Brandon M. Murphy, Xiaoyang Zhang, Eric L. Snyder
The ability of cancer cells to undergo identity changes (i.e., lineage plasticity) plays a key role in tumor progression and response to therapy. Loss of the pulmonary lineage specifier NKX2-1 in KRAS-driven lung adenocarcinoma (LUAD) enhances tumor progression and causes a FoxA1/2-dependent pulmonary-to-gastric lineage switch. However, the mechanisms by which FoxA1/2 activate a latent gastric identity in the lung remain largely unknown. Here, we show that FoxA1/2 reprogram the epigenetic landscape of gastric-specific genes after NKX2-1 loss in mouse models by facilitating ten-eleven translocation (TET)2/3 recruitment, DNA demethylation, histone 3 lysine 27 acetylation (H3K27ac) deposition, and three-dimensional (3D) chromatin interactions. FoxA1/2-mediated DNA methylation changes are highly conserved in human endodermal development and in progression of human lung and pancreatic neoplasia. Furthermore, oncogenic signaling is required for specific elements of FoxA1/2-dependent epigenetic reprogramming. This work demonstrates the role of FoxA1/2 in rewiring the DNA methylation and 3D chromatin landscape of NKX2-1-negative LUAD to drive cancer cell lineage switching.
{"title":"FoxA1/2-dependent epigenomic reprogramming drives lineage switching in lung adenocarcinoma","authors":"Katherine Gillis, Walter A. Orellana, Emily Wilson, Timothy J. Parnell, Gabriela Fort, Pengshu Fang, Headtlove Essel Dadzie, Brandon M. Murphy, Xiaoyang Zhang, Eric L. Snyder","doi":"10.1016/j.devcel.2024.10.009","DOIUrl":"https://doi.org/10.1016/j.devcel.2024.10.009","url":null,"abstract":"The ability of cancer cells to undergo identity changes (i.e., lineage plasticity) plays a key role in tumor progression and response to therapy. Loss of the pulmonary lineage specifier NKX2-1 in KRAS-driven lung adenocarcinoma (LUAD) enhances tumor progression and causes a FoxA1/2-dependent pulmonary-to-gastric lineage switch. However, the mechanisms by which FoxA1/2 activate a latent gastric identity in the lung remain largely unknown. Here, we show that FoxA1/2 reprogram the epigenetic landscape of gastric-specific genes after NKX2-1 loss in mouse models by facilitating ten-eleven translocation (TET)2/3 recruitment, DNA demethylation, histone 3 lysine 27 acetylation (H3K27ac) deposition, and three-dimensional (3D) chromatin interactions. FoxA1/2-mediated DNA methylation changes are highly conserved in human endodermal development and in progression of human lung and pancreatic neoplasia. Furthermore, oncogenic signaling is required for specific elements of FoxA1/2-dependent epigenetic reprogramming. This work demonstrates the role of FoxA1/2 in rewiring the DNA methylation and 3D chromatin landscape of NKX2-1-negative LUAD to drive cancer cell lineage switching.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"3 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142594593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Neutrophils in the tumor microenvironment (TME) are heterogeneous populations associated with cancer prognosis and immunotherapy. However, the plasticity and function of heterogeneous neutrophils in the TME of non-small-cell lung cancer (NSCLC) remain unclear. Here, we show that neutrophils produce high levels of interleukin (IL)-8, which induce the differentiation of CD74highSiglecFlow neutrophils and suppress the generation of CD74lowSiglecFhigh neutrophils in the TME of IL-8-humanized NSCLC mice. The CD74highSiglecFlow neutrophils boost anti-tumor T cell responses via antigen cross-presentation. Deleting CD74 in IL-8-humanized neutrophils impairs T cell activation and exacerbates NSCLC progression, whereas a CD74 agonist enhances T cell activation and the efficacy of anti-programmed cell death 1 (PD-1) or osimertinib therapies. Additionally, the CD74highCD63low neutrophils in the TME and peripheral blood of advanced NSCLC patients phenocopy the CD74highSiglecFlow neutrophils in the TME of NSCLC mice and correlate well with the responsiveness to anti-PD-1 plus chemotherapies. These findings demonstrate an IL-8-CD74high neutrophil axis that promotes anti-tumor immunity in NSCLC.
{"title":"A subset of neutrophils activates anti-tumor immunity and inhibits non-small-cell lung cancer progression","authors":"Zhen Tang, Jing Hu, Xu-Chang Li, Wei Wang, Han-Yue Zhang, Yu-Yao Guo, Xin Shuai, Qian Chu, Conghua Xie, Dandan Lin, Bo Zhong","doi":"10.1016/j.devcel.2024.10.010","DOIUrl":"https://doi.org/10.1016/j.devcel.2024.10.010","url":null,"abstract":"Neutrophils in the tumor microenvironment (TME) are heterogeneous populations associated with cancer prognosis and immunotherapy. However, the plasticity and function of heterogeneous neutrophils in the TME of non-small-cell lung cancer (NSCLC) remain unclear. Here, we show that neutrophils produce high levels of interleukin (IL)-8, which induce the differentiation of CD74<sup>high</sup>SiglecF<sup>low</sup> neutrophils and suppress the generation of CD74<sup>low</sup>SiglecF<sup>high</sup> neutrophils in the TME of IL-8-humanized NSCLC mice. The CD74<sup>high</sup>SiglecF<sup>low</sup> neutrophils boost anti-tumor T cell responses via antigen cross-presentation. Deleting CD74 in IL-8-humanized neutrophils impairs T cell activation and exacerbates NSCLC progression, whereas a CD74 agonist enhances T cell activation and the efficacy of anti-programmed cell death 1 (PD-1) or osimertinib therapies. Additionally, the CD74<sup>high</sup>CD63<sup>low</sup> neutrophils in the TME and peripheral blood of advanced NSCLC patients phenocopy the CD74<sup>high</sup>SiglecF<sup>low</sup> neutrophils in the TME of NSCLC mice and correlate well with the responsiveness to anti-PD-1 plus chemotherapies. These findings demonstrate an IL-8-CD74<sup>high</sup> neutrophil axis that promotes anti-tumor immunity in NSCLC.","PeriodicalId":11157,"journal":{"name":"Developmental cell","volume":"95 1","pages":""},"PeriodicalIF":11.8,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142594592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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