Genes & development最新文献

{"title":"A developmental mechanism to regulate alternative polyadenylation in an adult stem cell lineage.","authors":"Lorenzo Gallicchio, Neuza R Matias, Fabián Morales-Polanco, Iliana Nava, Sarah Stern, Yi Zeng, Margaret T Fuller","doi":"10.1101/gad.351649.124","DOIUrl":"10.1101/gad.351649.124","url":null,"abstract":"<p><p>Alternative cleavage and polyadenylation (APA) often results in production of mRNA isoforms with either longer or shorter 3' UTRs from the same genetic locus, potentially impacting mRNA translation, localization, and stability. Developmentally regulated APA can thus make major contributions to cell type-specific gene expression programs as cells differentiate. During <i>Drosophila</i> spermatogenesis, ∼500 genes undergo APA when proliferating spermatogonia differentiate into spermatocytes, producing transcripts with shortened 3' UTRs, leading to profound stage-specific changes in the proteins expressed. The molecular mechanisms that specify usage of upstream polyadenylation sites in spermatocytes are thus key to understanding the changes in cell state. Here, we show that upregulation of PCF11 and Cbc, the two components of cleavage factor II (CFII), orchestrates APA during <i>Drosophila</i> spermatogenesis. Knockdown of <i>PCF11</i> or <i>cbc</i> in spermatocytes caused dysregulation of APA, with many transcripts normally cleaved at a proximal site in spermatocytes now cleaved at their distal site, as in spermatogonia. Forced overexpression of CFII components in spermatogonia switched cleavage of some transcripts to the proximal site normally used in spermatocytes. Our findings reveal a developmental mechanism where changes in expression of specific cleavage factors can direct cell type-specific APA at selected genes.</p>","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":"655-674"},"PeriodicalIF":7.5,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11368245/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141901428","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hyd/UBR5 defines a tumor suppressor pathway that links Polycomb repressive complex to regulated protein degradation in tissue growth control and tumorigenesis.","authors":"Pei Wen, Huiyan Lei, Hua Deng, Su Deng, Carla Rodriguez Tirado, Meiling Wang, Ping Mu, Yonggang Zheng, Duojia Pan","doi":"10.1101/gad.351856.124","DOIUrl":"10.1101/gad.351856.124","url":null,"abstract":"<p><p>Tumor suppressor genes play critical roles in normal tissue homeostasis, and their dysregulation underlies human diseases including cancer. Besides human genetics, model organisms such as <i>Drosophila</i> have been instrumental in discovering tumor suppressor pathways that were subsequently shown to be highly relevant in human cancer. Here we show that hyperplastic disc (Hyd), one of the first tumor suppressors isolated genetically in <i>Drosophila</i> and encoding an E3 ubiquitin ligase with hitherto unknown substrates, and Lines (Lin), best known for its role in embryonic segmentation, define an obligatory tumor suppressor protein complex (Hyd-Lin) that targets the zinc finger-containing oncoprotein Bowl for ubiquitin-mediated degradation, with Lin functioning as a substrate adaptor to recruit Bowl to Hyd for ubiquitination. Interestingly, the activity of the Hyd-Lin complex is directly inhibited by a micropeptide encoded by another zinc finger gene, <i>drumstick</i> (<i>drm</i>), which functions as a pseudosubstrate by displacing Bowl from the Hyd-Lin complex, thus stabilizing Bowl. We further identify the epigenetic regulator Polycomb repressive complex1 (PRC1) as a critical upstream regulator of the Hyd-Lin-Bowl pathway by directly repressing the transcription of the micropeptide <i>drm</i> Consistent with these molecular studies, we show that genetic inactivation of Hyd, Lin, or PRC1 resulted in Bowl-dependent hyperplastic tissue overgrowth in vivo. We also provide evidence that the mammalian homologs of Hyd (UBR5, known to be recurrently dysregulated in various human cancers), Lin (LINS1), and Bowl (OSR1/2) constitute an analogous protein degradation pathway in human cells, and that OSR2 promotes prostate cancer tumorigenesis. Altogether, these findings define a previously unrecognized tumor suppressor pathway that links epigenetic program to regulated protein degradation in tissue growth control and tumorigenesis.</p>","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":"675-691"},"PeriodicalIF":7.5,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11368183/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tolerance thresholds underlie responses to DNA damage during germline development.","authors":"Gloria Jansen, Daniel Gebert, Tharini Ravindra Kumar, Emily Simmons, Sarah Murphy, Felipe Karam Teixeira","doi":"10.1101/gad.351701.124","DOIUrl":"10.1101/gad.351701.124","url":null,"abstract":"<p><p>Selfish DNA modules like transposable elements (TEs) are particularly active in the germline, the lineage that passes genetic information across generations. New TE insertions can disrupt genes and impair the functionality and viability of germ cells. However, we found that in <i>P</i>-<i>M</i> hybrid dysgenesis in <i>Drosophila</i>, a sterility syndrome triggered by the <i>P</i>-element DNA transposon, germ cells harbor unexpectedly few new TE insertions despite accumulating DNA double-strand breaks (DSBs) and inducing cell cycle arrest. Using an engineered CRISPR-Cas9 system, we show that generating DSBs at silenced <i>P</i>-elements or other noncoding sequences is sufficient to induce germ cell loss independently of gene disruption. Indeed, we demonstrate that both developing and adult mitotic germ cells are sensitive to DSBs in a dosage-dependent manner. Following the mitotic-to-meiotic transition, however, germ cells become more tolerant to DSBs, completing oogenesis regardless of the accumulated genome damage. Our findings establish DNA damage tolerance thresholds as crucial safeguards of genome integrity during germline development.</p>","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":"631-654"},"PeriodicalIF":7.5,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11368186/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141758199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum: XBP-1 deficiency in the nervous system protects against amyotrophic lateral sclerosis by increasing autophagy.","authors":"Claudio Hetz, Peter Thielen, Soledad Matus, Melissa Nassif, Felipe Court, Roberta Kiffin, Gabriela Martinez, Ana Maria Cuervo, Robert H Brown, Laurie H Glimcher","doi":"10.1101/gad.352249.124","DOIUrl":"10.1101/gad.352249.124","url":null,"abstract":"","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"38 15-16","pages":"785"},"PeriodicalIF":7.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11444174/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142283949","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum: TAp73 is a central transcriptional regulator of airway multiciliogenesis.","authors":"Alice Nemajerova, Daniela Kramer, Saul S Siller, Christian Herr, Orr Shomroni, Tonatiuh Pena, Cristina Gallinas Suazo, Katharina Glaser, Merit Wildung, Henrik Steffen, Anusha Sriraman, Fabian Oberle, Magdalena Wienken, Magali Hennion, Ramon Vidal, Bettina Royen, Mihai Alevra, Detlev Schild, Robert Bals, Jürgen Dönitz, Dietmar Riedel, Stefan Bonn, Ken-Ichi Takemaru, Ute M Moll, Muriel Lizé","doi":"10.1101/gad.352194.124","DOIUrl":"10.1101/gad.352194.124","url":null,"abstract":"","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"38 15-16","pages":"784"},"PeriodicalIF":7.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11444168/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142283948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparing the roles of sex chromosome-encoded protein homologs in gene regulation","authors":"Ellen Lavorando, Michael C. Owens, Kathy Fange Liu","doi":"10.1101/gad.351890.124","DOIUrl":"https://doi.org/10.1101/gad.351890.124","url":null,"abstract":"The X and Y chromosomes play important roles outside of human reproduction; namely, their potential contribution to human sex biases in physiology and disease. While sex biases are often thought to be an effect of hormones and environmental exposures, genes encoded on the sex chromosomes also play a role. Seventeen homologous gene pairs exist on the X and Y chromosomes whose proteins have critical functions in biology, from direct regulation of transcription and translation to intercellular signaling and formation of extracellular structures. In this review, we cover the current understanding of several of these sex chromosome-encoded protein homologs that are involved in transcription and chromatin regulation: SRY/SOX3, ZFX/ZFY, KDM5C/KDM5D, UTX/UTY, and TBL1X/TBL1Y. Their mechanisms of gene regulation are discussed, including any redundancies or divergent roles of the X- and Y-chromosome homologs. Additionally, we discuss associated diseases related to these proteins and any sex biases that exist therein in an effort to drive further research into how these pairs contribute to sexually dimorphic gene regulation in health and disease.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"23 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141754752","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":"SUMO promotes DNA repair protein collaboration to support alternative telomere lengthening in the absence of PML","authors":"Rongwei Zhao, Meng Xu, Xiaoyang Yu, Anne R. Wondisford, Rachel M. Lackner, Jayme Salsman, Graham Dellaire, David M. Chenoweth, Roderick J. O'Sullivan, Xiaolan Zhao, Huaiying Zhang","doi":"10.1101/gad.351667.124","DOIUrl":"https://doi.org/10.1101/gad.351667.124","url":null,"abstract":"The alternative lengthening of telomeres (ALT) pathway maintains telomere length in a significant fraction of cancers that are associated with poor clinical outcomes. A better understanding of ALT mechanisms is therefore necessary for developing new treatment strategies for ALT cancers. SUMO modification of telomere proteins contributes to the formation of ALT telomere-associated PML bodies (APBs), in which telomeres are clustered and DNA repair proteins are enriched to promote homology-directed telomere DNA synthesis in ALT. However, it is still unknown whether—and if so, how—SUMO supports ALT beyond APB formation. Here, we show that SUMO condensates that contain DNA repair proteins enable telomere maintenance in the absence of APBs. In PML knockout ALT cell lines that lack APBs, we found that SUMOylation is required for manifesting ALT features independent of PML and APBs. Chemically induced telomere targeting of SUMO produces condensate formation and ALT features in PML-null cells. This effect requires both SUMOylation and interactions between SUMO and SUMO interaction motifs (SIMs). Mechanistically, SUMO-induced effects are associated with the accumulation of DNA repair proteins, including Rad52, Rad51AP1, RPA, and BLM, at telomeres. Furthermore, Rad52 can undergo phase separation, enrich SUMO at telomeres, and promote telomere DNA synthesis in collaboration with the BLM helicase in a SUMO-dependent manner. Collectively, our findings suggest that SUMO condensate formation promotes collaboration among DNA repair factors to support ALT telomere maintenance without PML. Given the promising effects of SUMOylation inhibitors in cancer treatment, our findings suggest their potential use in perturbing telomere maintenance in ALT cancer cells.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"35 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141736867","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":"Structural and biochemical analyses of the nuclear IκBζ protein in complex with the NF-κB p50 homodimer.","authors":"Norman Zhu, W Eric Rogers, David K Heidary, Tom Huxford","doi":"10.1101/gad.351892.124","DOIUrl":"10.1101/gad.351892.124","url":null,"abstract":"<p><p>As part of the efforts to understand nuclear IκB function in NF-κB-dependent gene expression, we report an X-ray crystal structure of the IκBζ ankyrin repeat domain in complex with the dimerization domain of the NF-κB p50 homodimer. IκBζ possesses an N-terminal α helix that conveys domain folding stability. Affinity and specificity of the complex depend on a small portion of p50 at the nuclear localization signal. The model suggests that only one p50 subunit supports binding with IκBζ, and biochemical experiments confirm that IκBζ associates with DNA-bound NF-κB p50:RelA heterodimers. Comparisons of IκBζ:p50 and p50:κB DNA complex crystallographic models indicate that structural rearrangement is necessary for ternary complex formation of IκBζ and p50 with DNA.</p>","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":"528-535"},"PeriodicalIF":7.5,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11293385/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141497799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic modulators provide a path to understanding disease and therapeutic opportunity.","authors":"Madison A Honer, Benjamin I Ferman, Zach H Gray, Elena A Bondarenko, Johnathan R Whetstine","doi":"10.1101/gad.351444.123","DOIUrl":"10.1101/gad.351444.123","url":null,"abstract":"<p><p>The discovery of epigenetic modulators (writers, erasers, readers, and remodelers) has shed light on previously underappreciated biological mechanisms that promote diseases. With these insights, novel biomarkers and innovative combination therapies can be used to address challenging and difficult to treat disease states. This review highlights key mechanisms that epigenetic writers, erasers, readers, and remodelers control, as well as their connection with disease states and recent advances in associated epigenetic therapies.</p>","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":"473-503"},"PeriodicalIF":7.5,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11293403/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141446043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selective regulation of a defined subset of inflammatory and immunoregulatory genes by an NF-κB p50-IκBζ pathway.","authors":"Allison E Daly, George Yeh, Sofia Soltero, Stephen T Smale","doi":"10.1101/gad.351630.124","DOIUrl":"10.1101/gad.351630.124","url":null,"abstract":"<p><p>The five NF-κB family members and three nuclear IκB proteins play important biological roles, but the mechanisms by which distinct members of these protein families contribute to selective gene transcription remain poorly understood, especially at a genome-wide scale. Using nascent transcript RNA-seq, we observed considerable overlap between p50-dependent and IκBζ-dependent genes in Toll-like receptor 4 (TLR4)-activated macrophages. Key immunoregulatory genes, including <i>Il6</i>, <i>Il1b</i>, <i>Nos2</i>, <i>Lcn2,</i> and <i>Batf,</i> are among the p50-IκBζ-codependent genes. IκBζ-bound genomic sites are occupied at earlier time points by NF-κB dimers. However, p50-IκBζ codependence does not coincide with preferential binding of either p50 or IκBζ, as RelA co-occupies hundreds of genomic sites with the two proteins. A common feature of p50-IκBζ-codependent genes is a nearby p50/RelA/IκBζ-cobound site exhibiting p50-dependent binding of both RelA and IκBζ. This and other results suggest that IκBζ acts in concert with RelA:p50 heterodimers. Notably, p50-IκBζ-codependent genes comprise a high percentage of genes exhibiting the greatest differential expression between TLR4-stimulated and tumor necrosis factor receptor (TNFR)-stimulated macrophages. Thus, our genome-centric analysis reveals a defined p50-IκBζ pathway that selectively activates a set of key immunoregulatory genes and serves as an important contributor to differential TNFR and TLR4 responses.</p>","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":"536-553"},"PeriodicalIF":7.5,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11293394/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141450276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}