Genes & development最新文献

{"title":"The MYC-MAF-SAGA axis drives oncogenic gene expression in multiple myeloma.","authors":"Hongkuan Wang, Hong Wen, Xiaobing Shi","doi":"10.1101/gad.352186.124","DOIUrl":"10.1101/gad.352186.124","url":null,"abstract":"<p><p>The SAGA complex is an evolutionarily conserved histone acetyltransferase complex and transcription coactivator essential for development and disease. Dysregulation of SAGA is implicated in various human diseases, including cancer. In this issue of <i>Genes & Development,</i> Chen et al. (doi:10.1101/gad.351789.124) uncover a critical role for SAGA in multiple myeloma wherein SAGA's ADA2B component is required for the expression of mTORC1 pathway genes and targets of the MYC, E2F, and MAF (musculoaponeurotic fibrosarcoma) transcription factors. SAGA cooperates with MYC and MAF to sustain oncogenic gene expression programs vital for multiple myeloma survival and thus may serve as a therapeutic target for future cancer therapies.</p>","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":"693-694"},"PeriodicalIF":7.5,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11444177/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016908","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":"A cellular identity crisis? Plasticity changes during aging and rejuvenation","authors":"Rebecca Gorelov, Konrad Hochedlinger","doi":"10.1101/gad.351728.124","DOIUrl":"https://doi.org/10.1101/gad.351728.124","url":null,"abstract":"Cellular plasticity in adult multicellular organisms is a protective mechanism that allows certain tissues to regenerate in response to injury. Considering that aging involves exposure to repeated injuries over a lifetime, it is conceivable that cell identity itself is more malleable—and potentially erroneous—with age. In this review, we summarize and critically discuss the available evidence that cells undergo age-related shifts in identity, with an emphasis on those that contribute to age-associated pathologies, including neurodegeneration and cancer. Specifically, we focus on reported instances of programs associated with dedifferentiation, biased differentiation, acquisition of features from alternative lineages, and entry into a preneoplastic state. As some of the most promising approaches to rejuvenate cells reportedly also elicit transient changes to cell identity, we further discuss whether cell state change and rejuvenation can be uncoupled to yield more tractable therapeutic strategies.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"189 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245226","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":"Developmental regulation of dermal adipose tissue by BCL11b","authors":"Sarah Traynor, Shashwati Bhattacharya, Kirill Batmanov, Lan Cheng, Angela Weller, Natalie Moore, Carmen Flesher, David Merrick","doi":"10.1101/gad.351907.124","DOIUrl":"https://doi.org/10.1101/gad.351907.124","url":null,"abstract":"The distinct anatomic environment in which adipose tissues arise during organogenesis is a principle determinant of their adult expansion capacity. Metabolic disease results from a deficiency in hyperplastic adipose expansion within the dermal/subcutaneous depot; thus, understanding the embryonic origins of dermal adipose is imperative. Using single-cell transcriptomics throughout murine embryogenesis, we characterized cell populations, including <em>Bcl11b</em>^<em>+</em> cells, that regulate the development of dermal white adipose tissue (dWAT). We discovered that BCL11b expression modulates the Wnt signaling microenvironment to enable adipogenic differentiation in the dermal compartment. Subcutaneous and visceral adipose arises from a distinct population of <em>Nefl</em>^<em>+</em> cells during embryonic organogenesis, whereas <em>Pi16</em>^<em>+</em><em>/Dpp4</em>^<em>+</em> fibroadipogenic progenitors support obesity-stimulated hypertrophic expansion in the adult. Together, these results highlight the unique regulatory pathways used by anatomically distinct adipose depots, with important implications for human metabolic disease.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"20 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142175022","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":"Arrested development: the dysfunctional life history of medulloblastoma","authors":"Ran Tao, Katie Han, Stephanie C. Wu, Jake D. Friske, Martine F. Roussel, Paul A. Northcott","doi":"10.1101/gad.351936.124","DOIUrl":"https://doi.org/10.1101/gad.351936.124","url":null,"abstract":"Medulloblastoma is a heterogeneous embryonal tumor of the cerebellum comprised of four distinct molecular subgroups that differ in their developmental origins, genomic landscapes, clinical presentation, and survival. Recent characterization of the human fetal cerebellum at single-cell resolution has propelled unprecedented insights into the cellular origins of medulloblastoma subgroups, including those underlying previously elusive groups 3 and 4. In this review, the molecular pathogenesis of medulloblastoma is examined through the lens of cerebellar development. In addition, we discuss how enhanced understanding of medulloblastoma origins has the potential to refine disease modeling for the advancement of treatment and outcomes.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"8 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142130878","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":"Heterozygous RPA2 variant as a novel genetic cause of telomere biology disorders","authors":"Rima Kochman, Ibrahima Ba, Maïlyn Yates, Vithura Pirabakaran, Florian Gourmelon, Dmitri Churikov, Marc Lafaille, Laëtitia Kermasson, Coline Hamelin, Isabelle Marois, Frédéric Jourquin, Laura Braud, Marianne Bechara, Elodie Lainey, Hilario Nunes, Philippe Breton, Morgane Penhouet, Pierre David, Vincent Géli, Christophe Lachaud, Alexandre Maréchal, Patrick Revy, Caroline Kannengiesser, Carole Saintomé, Stéphane Coulon","doi":"10.1101/gad.352032.124","DOIUrl":"https://doi.org/10.1101/gad.352032.124","url":null,"abstract":"Premature telomere shortening or telomere instability is associated with a group of rare and heterogeneous diseases collectively known as telomere biology disorders (TBDs). Here we identified two unrelated individuals with clinical manifestations of TBDs and short telomeres associated with the identical monoallelic variant c.767A&gt;G; Y256C in <em>RPA2</em>. Although the replication protein A2 (RPA2) mutant did not affect ssDNA binding and G-quadruplex-unfolding properties of RPA, the mutation reduced the affinity of RPA2 with the ubiquitin ligase RFWD3 and reduced RPA ubiquitination. Using engineered knock-in cell lines, we found an accumulation of RPA at telomeres that did not trigger ATR activation but caused short and dysfunctional telomeres. Finally, both patients acquired, in a subset of blood cells, somatic genetic rescue events in either <em>POT1</em> genes or <em>TERT</em> promoters known to counteract the accelerated telomere shortening. Collectively, our study indicates that variants in <em>RPA2</em> represent a novel genetic cause of TBDs. Our results further support the fundamental role of the RPA complex in regulating telomere length and stability in humans.","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":"19 1","pages":""},"PeriodicalIF":10.5,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142130746","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":"What goes up must come down: off switches for regulatory RNAs.","authors":"Katherine McJunkin, Susan Gottesman","doi":"10.1101/gad.351934.124","DOIUrl":"10.1101/gad.351934.124","url":null,"abstract":"<p><p>Small RNAs base pair with and regulate mRNA translation and stability. For both bacterial small regulatory RNAs and eukaryotic microRNAs, association with partner proteins is critical for the stability and function of the regulatory RNAs. We review the mechanisms for degradation of these RNAs: displacement of the regulatory RNA from its protein partner (in bacteria) or destruction of the protein and its associated microRNAs (in eukaryotes). These mechanisms can allow specific destruction of a regulatory RNA via pairing with a decay trigger RNA or function as global off switches by disrupting the stability or function of the protein partner.</p>","PeriodicalId":12591,"journal":{"name":"Genes & development","volume":" ","pages":"597-613"},"PeriodicalIF":7.5,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11368247/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141901429","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":"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}