Genes & development最新文献_第4页

Active telomere elongation by a subclass of cancer-associated POT1 mutations 活性端粒延长与癌症相关的POT1突变亚类

IF 10.5 1区生物学

Genes & development Pub Date : 2025-02-27 DOI: 10.1101/gad.352492.124

Annika Martin, Johannes Schabort, Rebecca Bartke-Croughan, Stella Tran, Atul Preetham, Robert Lu, Richard Ho, Jianpu Gao, Shirin Jenkins, John Boyle, George E. Ghanim, Milind Jagota, Yun S. Song, Hanqin Li, Dirk Hockemeyer

{"title":"Active telomere elongation by a subclass of cancer-associated POT1 mutations","authors":"Annika Martin, Johannes Schabort, Rebecca Bartke-Croughan, Stella Tran, Atul Preetham, Robert Lu, Richard Ho, Jianpu Gao, Shirin Jenkins, John Boyle, George E. Ghanim, Milind Jagota, Yun S. Song, Hanqin Li, Dirk Hockemeyer","doi":"10.1101/gad.352492.124","DOIUrl":"https://doi.org/10.1101/gad.352492.124","url":null,"abstract":"Mutations in the shelterin protein POT1 are associated with diverse cancers and thought to drive carcinogenesis by impairing POT1's suppression of aberrant telomere elongation. To classify clinical variants of uncertain significance (VUSs) and identify cancer-driving loss-of-function mutations, we developed a locally haploid human stem cell system to evaluate >1900 POT1 mutations, including >600 VUSs. Unexpectedly, many validated familial cancer-associated POT1 (caPOT1) mutations are haplosufficient for cellular viability, indicating that some pathogenic alleles do not act through a loss-of-function mechanism. Instead, POT1's DNA damage response suppression and telomere length control are genetically separable. ATR inhibition enables isolation of frameshift mutants, demonstrating that the only essential function of POT1 is to repress ATR. Furthermore, comparison of caPOT1 and frameshift alleles reveals a class of caPOT1 mutations that elongate telomeres more rapidly than full loss-of-function alleles. This telomere length-promoting activity is independent from POT1's role in overhang sequestration and fill-in synthesis.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"9 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143518779","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}

引用次数: 0

The transcription factor SRF regulates MERVL retrotransposons and gene expression during zygotic genome activation 转录因子SRF调节MERVL逆转录转座子和合子基因组激活过程中的基因表达

IF 10.5 1区生物学

Genes & development Pub Date : 2025-02-27 DOI: 10.1101/gad.352270.124

Clara Hermant, Carlos Michel Mourra-Díaz, Marlies E. Oomen, Luis Altamirano-Pacheco, Mrinmoy Pal, Tsunetoshi Nakatani, Maria-Elena Torres-Padilla

{"title":"The transcription factor SRF regulates MERVL retrotransposons and gene expression during zygotic genome activation","authors":"Clara Hermant, Carlos Michel Mourra-Díaz, Marlies E. Oomen, Luis Altamirano-Pacheco, Mrinmoy Pal, Tsunetoshi Nakatani, Maria-Elena Torres-Padilla","doi":"10.1101/gad.352270.124","DOIUrl":"https://doi.org/10.1101/gad.352270.124","url":null,"abstract":"The regulatory circuitry of cell-specific transcriptional programs is thought to be influenced by transposable elements (TEs), whereby TEs serve as raw material for the diversification and genome-wide distribution of genetic elements that contain cis-regulatory activity. However, the transcriptional activators of TEs in relevant physiological contexts are largely unknown. Here, we undertook an evolutionary approach to identify regulators of two main families of MERVL, a major regulator of transcription during early mouse development. Using a combination of phyloregulatory, transcriptomic, and loss-of-function approaches, we demonstrate that SRF is a novel regulator of MERVL and embryonic transcription during zygotic genome activation. By resolving the phylogenetic history of two major MERVL families, we delineate the evolutionary acquisition of SRF and DUX binding sites and show that the acquisition of the SRF site precedes that of DUX. SRF contributes to embryonic transcription through the regulation of MERVLs, which in turn serve as promoters for host genes. Our work identifies new transcriptional regulators and TEs that shape the gene expression programs in early embryos and highlights the process of TE domestication via the sequential acquisition of transcription factor binding sites and coevolution with the host.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"52 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143518777","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}

引用次数: 0

Fatty acid uptake activates an AXL–CAV1–β-catenin axis to drive melanoma progression 脂肪酸摄取激活AXL-CAV1 -β-catenin轴驱动黑色素瘤进展

IF 10.5 1区生物学

Genes & development Pub Date : 2025-02-27 DOI: 10.1101/gad.351985.124

Ana Chocarro-Calvo, Miguel Jociles-Ortega, José Manuel García-Martinez, Pakavarin Louphrasitthiphol, Sofia Carvalho-Marques, Yurena Vivas-García, Ana Ramírez-Sánchez, Jagat Chauhan, M. Carmen Fiuza, Manuel Druan, Adriana Sánchez-Danés, Colin R. Goding, Custodia García-Jiménez

{"title":"Fatty acid uptake activates an AXL–CAV1–β-catenin axis to drive melanoma progression","authors":"Ana Chocarro-Calvo, Miguel Jociles-Ortega, José Manuel García-Martinez, Pakavarin Louphrasitthiphol, Sofia Carvalho-Marques, Yurena Vivas-García, Ana Ramírez-Sánchez, Jagat Chauhan, M. Carmen Fiuza, Manuel Druan, Adriana Sánchez-Danés, Colin R. Goding, Custodia García-Jiménez","doi":"10.1101/gad.351985.124","DOIUrl":"https://doi.org/10.1101/gad.351985.124","url":null,"abstract":"Interaction between the tumor microenvironment and cancer cell plasticity drives intratumor phenotypic heterogeneity and underpins disease progression and nongenetic therapy resistance. Phenotype-specific expression of the AXL receptor tyrosine kinase is a pivotal player in dormancy, invasion, and resistance to treatment. However, although the AXL ligand GAS6 is present within tumors, how AXL is activated in metastasizing cells remains unclear. Here, using melanoma as a model, we reveal that AXL is activated by exposure to human adipocytes and to oleic acid, a monounsaturated fatty acid abundant in lymph and in adipocytes. AXL activation triggers SRC-dependent formation and nuclear translocation of a β-catenin–CAV1 complex required for melanoma invasiveness. Remarkably, only undifferentiated AXLHigh melanoma cells engage in symbiosis with human adipocytes, in part by triggering WNT5a-mediated lipolysis, leading to AXL-dependent, but FATP-independent, fatty acid uptake and nuclear localization of the β-catenin–CAV1 complex. Significantly, human melanomas in the vicinity of adipocytes exhibit high levels of nuclear CAV1. The results unveil an AXL- and CAV1-dependent mechanism through which a nutritional input drives phenotype-specific activation of a prometastasis program. Given the key role of AXL in a broad range of cancers, the results offer major insights into the mechanisms of cancer cell dormancy and therapy resistance.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"33 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143518776","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}

引用次数: 0

RNA-binding proteins: it's better to play in a band rna结合蛋白：最好在乐队里演奏

IF 10.5 1区生物学

Genes & development Pub Date : 2025-02-12 DOI: 10.1101/gad.352667.125

Joshua Jeong, Klemens J. Hertel, Yongsheng Shi

引用次数: 0

Hao-Fountain syndrome protein USP7 controls neuronal differentiation via BCOR–ncPRC1.1 浩泉综合征蛋白USP7通过BCOR-ncPRC1.1调控神经元分化

IF 10.5 1区生物学

Genes & development Pub Date : 2025-02-07 DOI: 10.1101/gad.352272.124

Joyce Wolf van der Meer, Axelle Larue, Jan A. van der Knaap, Gillian E. Chalkley, Ayestha Sijm, Leila Beikmohammadi, Elena N. Kozhevnikova, Aniek van der Vaart, Ben C. Tilly, Karel Bezstarosti, Dick H.W. Dekkers, Wouter A.S. Doff, P. Jantine van de Wetering-Tieleman, Kristina Lanko, Tahsin Stefan Barakat, Tim Allertz, Jeffrey van Haren, Jeroen A.A. Demmers, Yaser Atlasi, C. Peter Verrijzer

{"title":"Hao-Fountain syndrome protein USP7 controls neuronal differentiation via BCOR–ncPRC1.1","authors":"Joyce Wolf van der Meer, Axelle Larue, Jan A. van der Knaap, Gillian E. Chalkley, Ayestha Sijm, Leila Beikmohammadi, Elena N. Kozhevnikova, Aniek van der Vaart, Ben C. Tilly, Karel Bezstarosti, Dick H.W. Dekkers, Wouter A.S. Doff, P. Jantine van de Wetering-Tieleman, Kristina Lanko, Tahsin Stefan Barakat, Tim Allertz, Jeffrey van Haren, Jeroen A.A. Demmers, Yaser Atlasi, C. Peter Verrijzer","doi":"10.1101/gad.352272.124","DOIUrl":"https://doi.org/10.1101/gad.352272.124","url":null,"abstract":"Pathogenic variants in the ubiquitin-specific protease 7 (USP7) gene cause a neurodevelopmental disorder called Hao-Fountain syndrome. However, it remains unclear which of USP7's pleiotropic functions are relevant for neurodevelopment. Here, we present a combination of quantitative proteomics, transcriptomics, and epigenomics to define the USP7 regulatory circuitry during neuronal differentiation. USP7 activity is required for the transcriptional programs that direct both the differentiation of embryonic stem cells into neural stem cells and the neuronal differentiation of SH-SY5Y neuroblastoma cells. USP7 controls the dosage of the Polycomb monubiquitylated histone H2A lysine 119 (H2AK119ub1) ubiquitin ligase complexes ncPRC1.1 and ncPRC1.6. Loss-of-function experiments revealed that BCOR–ncPRC1.1, but not ncPRC1.6, is a key effector of USP7 during neuronal differentiation. Indeed, BCOR–ncPRC1.1 mediates a major portion of USP7-dependent gene regulation during this process. Besides providing a detailed map of the USP7 regulome during neurodifferentiation, our results suggest that USP7- and ncPRC1.1-associated neurodevelopmental disorders involve dysregulation of a shared epigenetic network.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"15 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143367421","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}

引用次数: 0

The double life of mammalian DNA replication origins 哺乳动物DNA复制的双重生命起源

IF 10.5 1区生物学

Genes & development Pub Date : 2025-02-04 DOI: 10.1101/gad.352227.124

Olivier Hyrien, Guillaume Guilbaud, Torsten Krude

{"title":"The double life of mammalian DNA replication origins","authors":"Olivier Hyrien, Guillaume Guilbaud, Torsten Krude","doi":"10.1101/gad.352227.124","DOIUrl":"https://doi.org/10.1101/gad.352227.124","url":null,"abstract":"Mammalian DNA replication origins have been historically difficult to identify and their determinants are still unresolved. Here, we first review methods developed over the last decades to map replication initiation sites either directly via initiation intermediates or indirectly via determining replication fork directionality profiles. We also discuss the factors that may specify these sites as replication initiation sites. Second, we address the controversy that has emerged from these results over whether origins are narrowly defined and localized to specific sites or are more dispersed and organized into broad zones. Ample evidence in favor of both scenarios currently creates an impression of unresolved confusion in the field. We attempt to formulate a synthesis of both models and to reconcile discrepant findings. It is evident that not only one approach is sufficient in isolation but that the combination of several is instrumental toward understanding initiation sites in mammalian genomes. We argue that an aggregation of several individual and often inefficient initiation sites into larger initiation zones and the existence of efficient unidirectional initiation sites and fork stalling at the borders of initiation zones can reconcile the different observations.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"40 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143125163","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}

引用次数: 0

A feedback amplifier circuit with Notch and E2A orchestrates T-cell fate and suppresses the innate lymphoid cell lineages during thymic ontogeny 一个带有Notch和E2A的反馈放大电路在胸腺个体发生过程中协调t细胞的命运并抑制先天淋巴样细胞谱系

IF 10.5 1区生物学

Genes & development Pub Date : 2025-02-04 DOI: 10.1101/gad.352111.124

Kazuko Miyazaki, Kenta Horie, Hitomi Watanabe, Reiko Hidaka, Rinako Hayashi, Norihito Hayatsu, Kentaro Fujiwara, Rei Kuwata, Takuya Uehata, Yotaro Ochi, Makoto Takenaka, Risa Karakida Kawaguchi, Koichi Ikuta, Osamu Takeuchi, Seishi Ogawa, Katsuto Hozumi, Georg A. Holländer, Gen Kondoh, Taishin Akiyama, Masaki Miyazaki

{"title":"A feedback amplifier circuit with Notch and E2A orchestrates T-cell fate and suppresses the innate lymphoid cell lineages during thymic ontogeny","authors":"Kazuko Miyazaki, Kenta Horie, Hitomi Watanabe, Reiko Hidaka, Rinako Hayashi, Norihito Hayatsu, Kentaro Fujiwara, Rei Kuwata, Takuya Uehata, Yotaro Ochi, Makoto Takenaka, Risa Karakida Kawaguchi, Koichi Ikuta, Osamu Takeuchi, Seishi Ogawa, Katsuto Hozumi, Georg A. Holländer, Gen Kondoh, Taishin Akiyama, Masaki Miyazaki","doi":"10.1101/gad.352111.124","DOIUrl":"https://doi.org/10.1101/gad.352111.124","url":null,"abstract":"External signals from the thymic microenvironment and the activities of lineage-specific transcription factors (TFs) instruct T-cell versus innate lymphoid cell (ILC) fates. However, mechanistic insights into how factors such as Notch1–Delta-like-4 (Dll4) signaling and E-protein TFs collaborate to establish T-cell identity remain rudimentary. Using multiple in vivo approaches and single-cell multiome analysis, we identified a feedback amplifier circuit that specifies fetal and adult T-cell fates. In early T progenitors (ETPs) in the fetal thymus, Notch signaling minimally lowered E-protein antagonist Id2 levels, and high Id2 abundance favored the differentiation of ETPs into ILCs. Conversely, in the adult thymus, Notch signaling markedly decreased Id2 abundance in ETPs, substantially elevating E-protein DNA binding and in turn promoting the activation of a T-cell lineage-specific gene expression program linked with V(D)J gene recombination and T-cell receptor signaling. Our findings indicate that, in the fetal versus the adult thymus, a simple feedback amplifier circuit dictated by Notch-mediated signals and Id2 abundance enforces T-cell identity and suppresses ILC development.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"41 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143125221","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}

引用次数: 0

Corrigendum: Identification of a PTEN-regulated STAT3 brain tumor suppressor pathway 勘误：pten调控的STAT3脑肿瘤抑制通路的鉴定

IF 10.5 1区生物学

Genes & development Pub Date : 2025-02-01 DOI: 10.1101/gad.352503.124

Núria de la Iglesia, Genevieve Konopka, Sidharth V. Puram, Jennifer A. Chan, Robert M. Bachoo, Mingjian J. You, David E. Levy, Ronald A. DePinho, Azad Bonni

引用次数: 0

The Rbfox1/LASR complex controls alternative pre-mRNA splicing by recognition of multipart RNA regulatory modules Rbfox1/LASR复合体通过识别多部分RNA调控模块来控制备选的pre-mRNA剪接

IF 10.5 1区生物学

Genes & development Pub Date : 2025-01-29 DOI: 10.1101/gad.352105.124

Parham Peyda, Chia-Ho Lin, Kelechi Onwuzurike, Douglas L. Black

{"title":"The Rbfox1/LASR complex controls alternative pre-mRNA splicing by recognition of multipart RNA regulatory modules","authors":"Parham Peyda, Chia-Ho Lin, Kelechi Onwuzurike, Douglas L. Black","doi":"10.1101/gad.352105.124","DOIUrl":"https://doi.org/10.1101/gad.352105.124","url":null,"abstract":"The Rbfox proteins regulate alternative pre-mRNA splicing by binding to the RNA element GCAUG. In the nucleus, most of Rbfox is bound to the large assembly of splicing regulators (LASR), a complex of RNA-binding proteins that recognize additional RNA motifs. However, it remains unclear how the different subunits of the Rbfox/LASR complex act together to bind RNA and regulate splicing. We used a nuclease protection assay to map the transcriptome-wide footprints of Rbfox1/LASR on nascent cellular RNA. In addition to GCAUG, Rbfox1/LASR binds RNA motifs for LASR subunits hnRNPs M, H/F, and C and Matrin3. These elements are often arranged in tandem, forming multipart modules of RNA motifs. To distinguish contact sites of Rbfox1 from the LASR subunits, we analyzed a mutant Rbfox1(F125A) that has lost RNA binding but remains associated with LASR. Rbfox1(F125A)/LASR complexes no longer interact with GCAUG but retain binding to RNA elements for LASR. Splicing analyses reveal that in addition to activating exons through adjacent GCAUG elements, Rbfox can also stimulate exons near binding sites for LASR subunits. Minigene experiments demonstrate that these diverse elements produce a combined regulatory effect on a target exon. These findings illuminate how a complex of RNA-binding proteins can decode combinatorial splicing regulatory signals by recognizing groups of tandem RNA elements.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"207 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143056332","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}

引用次数: 0

Histone bivalency in CNS development 组蛋白二价在中枢神经系统发育中的作用

IF 10.5 1区生物学

Genes & development Pub Date : 2025-01-29 DOI: 10.1101/gad.352306.124

Kärt Mätlik, Eve-Ellen Govek, Mary E. Hatten

引用次数: 0