Genes & development最新文献

{"title":"Ribosome association inhibits stress-induced gene mRNA localization to stress granules","authors":"Noah S. Helton, Benjamin Dodd, Stephanie L. Moon","doi":"10.1101/gad.352899.125","DOIUrl":"https://doi.org/10.1101/gad.352899.125","url":null,"abstract":"The integrated stress response (ISR) is critical for resilience to stress and is implicated in numerous diseases. During the ISR, translation is repressed, stress-induced genes are expressed, and mRNAs condense into stress granules. The relationship between stress granules and stress-induced gene expression is unclear. We measured endogenous stress-induced gene mRNA localization at the single-molecule level in the presence or absence of small molecule translation inhibitors. Reducing ribosome association increases the localization of stress-induced gene mRNAs to stress granules, whereas increasing ribosome association inhibits their localization to stress granules. The presence of upstream open reading frames (uORFs) in mRNA reporters reduces their localization to stress granules in a ribosome-dependent manner. Furthermore, a single initiating ribosome blocks stress granule formation and inhibits mRNA association with preformed stress granules. Thus, uORF-mediated ribosome association inhibits stress-induced gene mRNA localization to stress granules, suggesting a new role for uORFs in limiting RNA condensation.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"701 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143945975","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}

{"title":"Cohesin in 3D: development, differentiation, and disease","authors":"Maria Solé-Ferran, Ana Losada","doi":"10.1101/gad.352671.125","DOIUrl":"https://doi.org/10.1101/gad.352671.125","url":null,"abstract":"Cohesin contributes to genome spatial organization and sister chromatid cohesion. In this way, it not only supports accurate chromosome segregation and efficient DNA repair but also regulates gene expression. These functions are essential during embryonic development, the process that converts the fertilized egg into a complex organism with billions of specialized cells organized into tissues and organs. Here, we briefly summarize current knowledge on how cohesin and its associated factors perform chromatin looping and cohesion. We then review studies addressing their contribution to cell differentiation and embryonic development. Finally, we discuss cohesinopathies, human developmental syndromes caused by cohesin dysfunction.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"229 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143930863","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}

{"title":"Drosha: a new tumor suppressor in pineoblastoma","authors":"Zhixuan Huang, Xueli Ren, Jian Hu","doi":"10.1101/gad.352932.125","DOIUrl":"https://doi.org/10.1101/gad.352932.125","url":null,"abstract":"To investigate the pathogenesis and target the vulnerability of human pineoblastoma, researchers have developed multiple genetically engineered mouse models that represent distinct molecular subtypes of the disease. In this issue of <em>Genes &amp; Development</em>, Fraire and colleagues (doi:10.1101/gad.352485.124) examined the roles of key microRNA (miRNA) processing components Drosha and Dicer1. Loss of either <em>Drosha</em> or <em>Dicer1</em> partially mimicked the tumorigenic effects of <em>Rb1</em> deletion by promoting cell cycle progression through the derepression of Plagl2 and cyclin D2. This work reveals a novel mechanism of pineoblastoma development driven by disrupted miRNA processing and highlights a potential therapeutic strategy targeting downstream proliferative drivers.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"7 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143930862","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}

{"title":"Aneuploidy generates enhanced nucleotide dependency and sensitivity to metabolic perturbation","authors":"Rayna Y. Magesh, Arshia N. Kaur, Faith N. Keller, Abdulrazak Frederick, Tenzin Tseyang, John A. Haley, Alejandra M. Rivera-Nieves, Anthony C. Liang, David A. Guertin, Jessica B. Spinelli, Stephen J. Elledge, Emma V. Watson","doi":"10.1101/gad.352512.124","DOIUrl":"https://doi.org/10.1101/gad.352512.124","url":null,"abstract":"Despite the general detriment of aneuploidy to cellular fitness, &gt;90% of solid tumors carry an imbalanced karyotype. This existing paradox and the molecular responses to aneuploidy remain poorly understood. Here, we explore these cellular stresses and unique vulnerabilities of aneuploidy in human mammary epithelial cells (HMECs) enriched for breast cancer-associated copy number alterations (CNAs). To uncover the genetic dependencies specific to aneuploid cells, we conducted a comprehensive, genome-wide CRISPR knockout screen in isogenic aneuploid and diploid HMEC lines. Our study reveals that aneuploid HMECs exhibit an increased reliance on pyrimidine biosynthesis and mitochondrial oxidative phosphorylation genes and demonstrate heightened fitness advantages upon loss of tumor suppressor genes. Using an integrative multiomic analysis, we confirmed nucleotide pool insufficiency as a key contributor to widespread cellular dysfunction in aneuploid HMECs with net copy number gain. Although diploid cells can switch seamlessly between pyrimidine synthesis and salvage, cells with increased chromosomal content exhibit p53 activation and S-phase arrest when relying on salvage alone, alongside increased sensitivity to DNA-damaging chemotherapeutics. This work advances our understanding of the consequences of aneuploidy and uncovers potential avenues for patient stratification and therapeutic intervention based on tumor ploidy.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"1 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143909957","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}

{"title":"The rise of RAS: how gradual oncogene activation shapes the OIS spectrum","authors":"Haoran Zhu, Adelyne Sue Li Chan, Masashi Narita","doi":"10.1101/gad.352761.125","DOIUrl":"https://doi.org/10.1101/gad.352761.125","url":null,"abstract":"Excessive levels of oncogenic RAS expression in normal cells trigger reactive cellular senescence, known as oncogene-induced senescence (OIS)—a putative autonomous tumor-suppressive mechanism. However, the monoallelic expression of oncogenic RAS from the endogenous locus often fails to induce senescence, at least in the short term. Consequently, whether robust senescence characterizes the preneoplasia driven by oncogenic RAS under physiological conditions has been debated. A key challenge is the highly heterogeneous nature of senescence at both the population and single-cell levels. Notably, increasing evidence suggests that RAS levels are gradually upregulated during the development of tumors driven by oncogenic RAS. To address the complex relationship between diverse oncogenic responses, including senescence and tumor initiation, we introduce the concept of an OIS spectrum, where oncogenic dosage-dependent cellular states lie between normal cells and full senescence. Intermediate “sub-OIS” states may play a critical role in tumor initiation, potentially providing one explanation for the ongoing debate.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"11 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143909776","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}

{"title":"A distal enhancer with ETV4 binding is critical for UCP1 expression and thermogenesis in brown fat","authors":"Pengya Xue, Nicholas Holloway, Alexander Tran, Frances Lin, Jennie Dinh, Caleb Yang, Yuhui Wang, Danielle Yi, Hei Sook Sul","doi":"10.1101/gad.352748.125","DOIUrl":"https://doi.org/10.1101/gad.352748.125","url":null,"abstract":"Brown adipose tissue (BAT) dissipates energy as heat in maintaining body temperature, and BAT mass inversely correlates with adiposity. During thermogenesis, BAT generates heat by uncoupling respiration through UCP1, and the −2.5 kb enhancer of <em>UCP1</em> gene is known to activate <em>UCP1</em> expression upon cold or β-adrenergic stimulation. Here, we identify a critical <em>UCP1</em> enhancer located at 12 kb upstream of the <em>UCP1</em> gene locus that functions through chromatin looping and uncover its essential role in <em>UCP1</em> activation and thermogenesis by CRISPR activation and CRISPR interference in mice. Importantly, we identify ETV4 as a key regulator of <em>UCP1</em> expression by binding the −12 kb enhancer to promote chromatin accessibility and histone acetylation. Using gain- and loss-of-function approaches, we reveal that ETV4 enhances uncoupled respiration and thermogenesis, thereby protecting mice from diet-induced obesity and insulin resistance. The −12 kb enhancer and ETV4 can be potential therapeutic targets for combating obesity and improving metabolic health.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"11 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143909777","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}

{"title":"The USP11/TCEAL1 complex promotes transcription elongation to sustain oncogenic gene expression in neuroblastoma","authors":"Markus Dehmer, Katrin Trunk, Peter Gallant, Daniel Fleischhauer, Mareike Müller, Steffi Herold, Giacomo Cossa, Francesca Conte, Jan Koster, Florian Sauer, Christina Schülein-Völk, Carsten P. Ade, Raphael Vidal, Caroline Kisker, Rogier Versteeg, Petra Beli, Seychelle M. Vos, Martin Eilers, Gabriele Büchel","doi":"10.1101/gad.352166.124","DOIUrl":"https://doi.org/10.1101/gad.352166.124","url":null,"abstract":"During early transcription, RNA polymerase II (RNAPII) undergoes a series of structural transitions controlled by cyclin-dependent kinases. How protein ubiquitylation and proteasomal degradation control the function of RNAPII is less well understood. Here we show that the deubiquitinating enzyme USP11 forms a complex with TCEAL1, a member of the TFIIS (TCEA)-like protein family. TCEAL1 shares sequence homology with the RNAPII interaction domain of the elongation factor TFIIS (which controls the fate of backtracked RNAPII) and competes with TFIIS for binding to core promoters. USP11 protects TCEAL1 from proteasomal degradation, and TCEAL1 recruits USP11 to RNAPII. Both USP11 and TCEAL1 promote transcription elongation and maintain expression of RPB8, an essential subunit of all three nuclear RNA polymerases. In neuroblastoma, USP11- and TCEAL1-dependent genes define a gene expression program that is characteristic for mesenchymal tumors, which are described as able to escape from many treatments, suggesting that the USP11/TCEAL1 complex promotes transcription elongation to support a critical oncogenic gene expression program.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"31 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143849523","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}

{"title":"A boundary-defining protein facilitates megabase-scale regulatory chromosomal loop formation in Drosophila neurons","authors":"Marion Mouginot, Sahar Hani, Pascal Cousin, Julien Dorier, Arianna Ravera, Maria Cristina Gambetta","doi":"10.1101/gad.352646.125","DOIUrl":"https://doi.org/10.1101/gad.352646.125","url":null,"abstract":"Regulatory elements, such as enhancers and silencers, control transcription by establishing physical proximity to target gene promoters. Neurons in flies and mammals exhibit long-range three-dimensional genome contacts, proposed to connect genes with distal regulatory elements. However, the relevance of these contacts for neuronal gene transcription and the mechanisms underlying their specificity necessitate further investigation. Here, we precisely disrupt several long-range contacts in fly neurons, demonstrating their importance for megabase-range gene regulation and uncovering a hierarchical process in their formation. We further reveal an essential role for the chromosomal boundary-forming protein Cp190 in anchoring many long-range contacts, highlighting a mechanistic interplay between boundary and loop formation. Finally, we develop an unbiased proteomics-based method to systematically identify factors required for specific long-range contacts. Our findings underscore the essential role of architectural proteins such as Cp190 in cell type-specific genome organization in enabling specialized neuronal transcriptional programs.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"24 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143841187","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}

{"title":"Histone chaperones coupled to DNA replication and transcription control divergent chromatin elements to maintain cell fate","authors":"Reuben Franklin, Brian Zhang, Jonah Frazier, Meijuan Chen, Brian T. Do, Sally Padayao, Kun Wu, Matthew G. Vander Heiden, Christopher R. Vakoc, Jae-Seok Roe, Maria Ninova, Jernej Murn, David B. Sykes, Sihem Cheloufi","doi":"10.1101/gad.352316.124","DOIUrl":"https://doi.org/10.1101/gad.352316.124","url":null,"abstract":"The manipulation of DNA replication and transcription can be harnessed to control cell fate. Central to the regulation of these DNA-templated processes are histone chaperones, which in turn are emerging as cell fate regulators. Histone chaperones are a group of proteins with diverse functions that are primarily involved in escorting histones to assemble nucleosomes and maintain the chromatin landscape. Whether distinct histone chaperone pathways control cell fate and whether they function using related mechanisms remain unclear. To address this, we performed a screen to assess the requirement of diverse histone chaperones in the self-renewal of hematopoietic stem and progenitor cells. Remarkably, all candidates were required to maintain cell fate to differing extents, with no clear correlation with their specific histone partners or DNA-templated process. Among all the histone chaperones, the loss of the transcription-coupled histone chaperone SPT6 most strongly promoted differentiation, even more than the major replication-coupled chromatin assembly factor complex CAF-1. To directly compare how DNA replication- and transcription-coupled histone chaperones maintain stem cell self-renewal, we generated an isogenic dual-inducible system to perturb each pathway individually. We found that SPT6 and CAF-1 perturbations required cell division to induce differentiation but had distinct effects on cell cycle progression, chromatin accessibility, and lineage choice. CAF-1 depletion led to S-phase accumulation, increased heterochromatic accessibility (particularly at H3K27me3 sites), and aberrant multilineage gene expression. In contrast, SPT6 loss triggered cell cycle arrest, altered accessibility at promoter elements, and drove lineage-specific differentiation, which is in part influenced by AP-1 transcription factors. Thus, CAF-1 and SPT6 histone chaperones maintain cell fate through distinct mechanisms, highlighting how different chromatin assembly pathways can be leveraged to alter cell fate.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"38 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143841245","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}

{"title":"An imbalance between proliferation and differentiation underlies the development of microRNA-defective pineoblastoma","authors":"Claudette R. Fraire, Kavita Desai, Indumathy Jagadeeswaran, Uma A. Obalapuram, Lindsay K. Mendyka, Veena Rajaram, Teja Sebastian, Yemin Wang, Kenan Onel, Jeon Lee, Stephen X. Skapek, Kenneth S. Chen","doi":"10.1101/gad.352485.124","DOIUrl":"https://doi.org/10.1101/gad.352485.124","url":null,"abstract":"Mutations in the microRNA processing genes <em>DROSHA</em> and <em>DICER1</em> drive several cancers that resemble embryonic progenitors. To understand how microRNAs regulate tumorigenesis, we ablated <em>Drosha</em> or <em>Dicer1</em> in the developing pineal gland to emulate the pathogenesis of pineoblastoma, a brain tumor that resembles undifferentiated precursors of the pineal gland. Accordingly, these mice develop pineal tumors marked by loss of microRNAs, particularly the let-7/miR-98-5p family, and derepression of microRNA target genes. Pineal tumors driven by loss of <em>Drosha</em> or <em>Dicer1</em> mimic tumors driven by <em>Rb1</em> loss, as they exhibit upregulation of S-phase genes and homeobox transcription factors that regulate pineal development. Blocking proliferation of these tumors facilitates expression of pinealocyte maturation markers, with a concomitant reduction in embryonic markers. Select embryonic markers remain elevated, however, as the microRNAs that normally repress these target genes remain absent. One such microRNA target gene is the oncofetal transcription factor <em>Plagl2</em>, which regulates expression of progrowth genes, and inhibiting their signaling impairs tumor growth. Thus, we demonstrate that tumors driven by loss of microRNA processing may be therapeutically targeted by inhibiting downstream drivers of proliferation.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"5 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143841246","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}