Pub Date : 2024-11-20DOI: 10.1038/s41588-024-02021-0
Steven M. Lewis, Camila dos Santos
The two-hit hypothesis suggests that a second mutation is necessary for cancer development in cells with a defective tumor-suppressor gene, such as BRCA1. However, a study now shows that the loss of just one Brca1 allele in mice can pre-program cells for cancer-promoting changes, indicating cancer may progress earlier than previously thought.
{"title":"Epigenetic scars of Brca1 loss point toward breast cancer cell of origin","authors":"Steven M. Lewis, Camila dos Santos","doi":"10.1038/s41588-024-02021-0","DOIUrl":"10.1038/s41588-024-02021-0","url":null,"abstract":"The two-hit hypothesis suggests that a second mutation is necessary for cancer development in cells with a defective tumor-suppressor gene, such as BRCA1. However, a study now shows that the loss of just one Brca1 allele in mice can pre-program cells for cancer-promoting changes, indicating cancer may progress earlier than previously thought.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 12","pages":"2594-2595"},"PeriodicalIF":31.7,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142673218","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 : 2024-11-20DOI: 10.1038/s41588-024-01988-0
Marc J. Williams, Michael U. J. Oliphant, Vinci Au, Cathy Liu, Caroline Baril, Ciara O’Flanagan, Daniel Lai, Sean Beatty, Michael Van Vliet, Jacky CH Yiu, Lauren O’Connor, Walter L. Goh, Alicia Pollaci, Adam C. Weiner, Diljot Grewal, Andrew McPherson, Klarisa Norton, McKenna Moore, Vikas Prabhakar, Shailesh Agarwal, Judy E. Garber, Deborah A. Dillon, Sohrab P. Shah, Joan S. Brugge, Samuel Aparicio
The prevalence and nature of somatic copy number alterations (CNAs) in breast epithelium and their role in tumor initiation and evolution remain poorly understood. Using single-cell DNA sequencing (49,238 cells) of epithelium from BRCA1 and BRCA2 carriers or wild-type individuals, we identified recurrent CNAs (for example, 1q-gain and 7q, 10q, 16q and 22q-loss) that are present in a rare population of cells across almost all samples (n = 28). In BRCA1/BRCA2 carriers, these occur before loss of heterozygosity (LOH) of wild-type alleles. These CNAs, common in malignant tumors, are enriched in luminal cells but absent in basal myoepithelial cells. Allele-specific analysis of prevalent CNAs reveals that they arose by independent mutational events, consistent with convergent evolution. BRCA1/BRCA2 carriers contained a small percentage of cells with extreme aneuploidy, featuring loss of TP53, BRCA1/BRCA2 LOH and multiple breast cancer-associated CNAs. Our findings suggest that CNAs arising in normal luminal breast epithelium are precursors to clonally expanded tumor genomes. Single-cell DNA sequencing identifies recurrent copy number changes in healthy breast tissue from women with wild-type or germline BRCA1 or BRCA2 mutations.
{"title":"Luminal breast epithelial cells of BRCA1 or BRCA2 mutation carriers and noncarriers harbor common breast cancer copy number alterations","authors":"Marc J. Williams, Michael U. J. Oliphant, Vinci Au, Cathy Liu, Caroline Baril, Ciara O’Flanagan, Daniel Lai, Sean Beatty, Michael Van Vliet, Jacky CH Yiu, Lauren O’Connor, Walter L. Goh, Alicia Pollaci, Adam C. Weiner, Diljot Grewal, Andrew McPherson, Klarisa Norton, McKenna Moore, Vikas Prabhakar, Shailesh Agarwal, Judy E. Garber, Deborah A. Dillon, Sohrab P. Shah, Joan S. Brugge, Samuel Aparicio","doi":"10.1038/s41588-024-01988-0","DOIUrl":"10.1038/s41588-024-01988-0","url":null,"abstract":"The prevalence and nature of somatic copy number alterations (CNAs) in breast epithelium and their role in tumor initiation and evolution remain poorly understood. Using single-cell DNA sequencing (49,238 cells) of epithelium from BRCA1 and BRCA2 carriers or wild-type individuals, we identified recurrent CNAs (for example, 1q-gain and 7q, 10q, 16q and 22q-loss) that are present in a rare population of cells across almost all samples (n = 28). In BRCA1/BRCA2 carriers, these occur before loss of heterozygosity (LOH) of wild-type alleles. These CNAs, common in malignant tumors, are enriched in luminal cells but absent in basal myoepithelial cells. Allele-specific analysis of prevalent CNAs reveals that they arose by independent mutational events, consistent with convergent evolution. BRCA1/BRCA2 carriers contained a small percentage of cells with extreme aneuploidy, featuring loss of TP53, BRCA1/BRCA2 LOH and multiple breast cancer-associated CNAs. Our findings suggest that CNAs arising in normal luminal breast epithelium are precursors to clonally expanded tumor genomes. Single-cell DNA sequencing identifies recurrent copy number changes in healthy breast tissue from women with wild-type or germline BRCA1 or BRCA2 mutations.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 12","pages":"2753-2762"},"PeriodicalIF":31.7,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01988-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142678346","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}
Pub Date : 2024-11-20DOI: 10.1038/s41588-024-01990-6
Christina Steyn, Ruvimbo Mishi, Stephanie Fillmore, Matthijs B. Verhoog, Jessica More, Ursula K. Rohlwink, Roger Melvill, James Butler, Johannes M. N. Enslin, Muazzam Jacobs, Tatjana Sauka-Spengler, Maria Greco, Sadi Quiñones, Chris G. Dulla, Joseph V. Raimondo, Anthony Figaji, Dorit Hockman
The human brain undergoes protracted postnatal maturation, guided by dynamic changes in gene expression. Most studies exploring these processes have used bulk tissue analyses, which mask cell-type-specific gene expression dynamics. Here, using single-nucleus RNA sequencing on temporal lobe tissue, including samples of African ancestry, we build a joint pediatric and adult atlas of 75 cell subtypes, which we verify with spatial transcriptomics. We explore the differences between pediatric and adult cell subtypes, revealing the genes and pathways that change during brain maturation. Our results highlight excitatory neuron subtypes, including the LTK and FREM subtypes, that show elevated expression of genes associated with cognition and synaptic plasticity in pediatric tissue. The resources we present here improve our understanding of the brain during its development and contribute to global efforts to build an inclusive brain cell map. This Pediatric Cell Atlas study analyzes temporal cortex single-nucleus RNA sequencing datasets from eight diverse donors from 4 to 50 years of age, describing gene expression dynamics over the course of brain maturation.
人脑在基因表达动态变化的引导下经历了漫长的产后成熟过程。大多数探索这些过程的研究都使用了大块组织分析，这掩盖了细胞类型特异性基因表达的动态变化。在这里，我们利用对颞叶组织（包括非洲血统样本）的单核 RNA 测序，建立了 75 种细胞亚型的儿科和成人联合图谱，并通过空间转录组学进行了验证。我们探索了小儿和成人细胞亚型之间的差异，揭示了大脑成熟过程中发生变化的基因和通路。我们的研究结果突显了兴奋性神经元亚型，包括 LTK 和 FREM 亚型，这些亚型在小儿组织中显示出与认知和突触可塑性相关基因的高表达。我们在此介绍的资源增进了我们对大脑发育过程的了解，并有助于全球构建包容性脑细胞图谱的努力。
{"title":"A temporal cortex cell atlas highlights gene expression dynamics during human brain maturation","authors":"Christina Steyn, Ruvimbo Mishi, Stephanie Fillmore, Matthijs B. Verhoog, Jessica More, Ursula K. Rohlwink, Roger Melvill, James Butler, Johannes M. N. Enslin, Muazzam Jacobs, Tatjana Sauka-Spengler, Maria Greco, Sadi Quiñones, Chris G. Dulla, Joseph V. Raimondo, Anthony Figaji, Dorit Hockman","doi":"10.1038/s41588-024-01990-6","DOIUrl":"10.1038/s41588-024-01990-6","url":null,"abstract":"The human brain undergoes protracted postnatal maturation, guided by dynamic changes in gene expression. Most studies exploring these processes have used bulk tissue analyses, which mask cell-type-specific gene expression dynamics. Here, using single-nucleus RNA sequencing on temporal lobe tissue, including samples of African ancestry, we build a joint pediatric and adult atlas of 75 cell subtypes, which we verify with spatial transcriptomics. We explore the differences between pediatric and adult cell subtypes, revealing the genes and pathways that change during brain maturation. Our results highlight excitatory neuron subtypes, including the LTK and FREM subtypes, that show elevated expression of genes associated with cognition and synaptic plasticity in pediatric tissue. The resources we present here improve our understanding of the brain during its development and contribute to global efforts to build an inclusive brain cell map. This Pediatric Cell Atlas study analyzes temporal cortex single-nucleus RNA sequencing datasets from eight diverse donors from 4 to 50 years of age, describing gene expression dynamics over the course of brain maturation.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 12","pages":"2718-2730"},"PeriodicalIF":31.7,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01990-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142678342","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}
Pub Date : 2024-11-20DOI: 10.1038/s41588-024-01993-3
Can Ergen, Galen Xing, Chenling Xu, Martin Kim, Michael Jayasuriya, Erin McGeever, Angela Oliveira Pisco, Aaron Streets, Nir Yosef
Cell-type classification is a crucial step in single-cell sequencing analysis. Various methods have been proposed for transferring a cell-type label from an annotated reference atlas to unannotated query datasets. Existing methods for transferring cell-type labels lack proper uncertainty estimation for the resulting annotations, limiting interpretability and usefulness. To address this, we propose popular Vote (popV), an ensemble of prediction models with an ontology-based voting scheme. PopV achieves accurate cell-type labeling and provides uncertainty scores. In multiple case studies, popV confidently annotates the majority of cells while highlighting cell populations that are challenging to annotate by label transfer. This additional step helps to reduce the load of manual inspection, which is often a necessary component of the annotation process, and enables one to focus on the most problematic parts of the annotation, streamlining the overall annotation process. Popular Vote (popV) is a simple, ensemble popular vote approach for cell type annotation in single-cell omic data, flexibly incorporating various methods in an open-source Python framework. Across various challenging input datasets, popV offers consistent, accurate performance.
{"title":"Consensus prediction of cell type labels in single-cell data with popV","authors":"Can Ergen, Galen Xing, Chenling Xu, Martin Kim, Michael Jayasuriya, Erin McGeever, Angela Oliveira Pisco, Aaron Streets, Nir Yosef","doi":"10.1038/s41588-024-01993-3","DOIUrl":"10.1038/s41588-024-01993-3","url":null,"abstract":"Cell-type classification is a crucial step in single-cell sequencing analysis. Various methods have been proposed for transferring a cell-type label from an annotated reference atlas to unannotated query datasets. Existing methods for transferring cell-type labels lack proper uncertainty estimation for the resulting annotations, limiting interpretability and usefulness. To address this, we propose popular Vote (popV), an ensemble of prediction models with an ontology-based voting scheme. PopV achieves accurate cell-type labeling and provides uncertainty scores. In multiple case studies, popV confidently annotates the majority of cells while highlighting cell populations that are challenging to annotate by label transfer. This additional step helps to reduce the load of manual inspection, which is often a necessary component of the annotation process, and enables one to focus on the most problematic parts of the annotation, streamlining the overall annotation process. Popular Vote (popV) is a simple, ensemble popular vote approach for cell type annotation in single-cell omic data, flexibly incorporating various methods in an open-source Python framework. Across various challenging input datasets, popV offers consistent, accurate performance.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 12","pages":"2731-2738"},"PeriodicalIF":31.7,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01993-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142678343","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}
Pub Date : 2024-11-20DOI: 10.1038/s41588-024-02034-9
Carman Man-Chung Li, Alyssa Cordes, Michael U. J. Oliphant, S. Aidan Quinn, Mayura Thomas, Laura M. Selfors, Francesca Silvestri, Nomeda Girnius, Gianmarco Rinaldi, Jason J. Zoeller, Hana Shapiro, Christina Tsiobikas, Kushali P. Gupta, Shailja Pathania, Aviv Regev, Cigall Kadoch, Senthil K. Muthuswamy, Joan S. Brugge
{"title":"Author Correction: Brca1 haploinsufficiency promotes early tumor onset and epigenetic alterations in a mouse model of hereditary breast cancer","authors":"Carman Man-Chung Li, Alyssa Cordes, Michael U. J. Oliphant, S. Aidan Quinn, Mayura Thomas, Laura M. Selfors, Francesca Silvestri, Nomeda Girnius, Gianmarco Rinaldi, Jason J. Zoeller, Hana Shapiro, Christina Tsiobikas, Kushali P. Gupta, Shailja Pathania, Aviv Regev, Cigall Kadoch, Senthil K. Muthuswamy, Joan S. Brugge","doi":"10.1038/s41588-024-02034-9","DOIUrl":"10.1038/s41588-024-02034-9","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 12","pages":"2842-2842"},"PeriodicalIF":31.7,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-02034-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142673169","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}
Pub Date : 2024-11-18DOI: 10.1038/s41588-024-01971-9
Samson H. Fong, Brent M. Kuenzi, Nicole M. Mattson, John Lee, Kyle Sanchez, Ana Bojorquez-Gomez, Kyle Ford, Brenton P. Munson, Katherine Licon, Sarah Bergendahl, John Paul Shen, Jason F. Kreisberg, Prashant Mali, Jeffrey H. Hager, Michael A. White, Trey Ideker
Cancers are driven by alterations in diverse genes, creating dependencies that can be therapeutically targeted. However, many genetic dependencies have proven inconsistent across tumors. Here we describe SCHEMATIC, a strategy to identify a core network of highly penetrant, actionable genetic interactions. First, fundamental cellular processes are perturbed by systematic combinatorial knockouts across tumor lineages, identifying 1,805 synthetic lethal interactions (95% unreported). Interactions are then analyzed by hierarchical pooling, revealing that half segregate reliably by tissue type or biomarker status (51%) and a substantial minority are penetrant across lineages (34%). Interactions converge on 49 multigene systems, including MAPK signaling and BAF transcriptional regulatory complexes, which become essential on disruption of polymerases. Some 266 interactions translate to robust biomarkers of drug sensitivity, including frequent genetic alterations in the KDM5C/6A histone demethylases, which sensitize to inhibition of TIPARP (PARP7). SCHEMATIC offers a context-aware, data-driven approach to match genetic alterations to targeted therapies.
{"title":"A multilineage screen identifies actionable synthetic lethal interactions in human cancers","authors":"Samson H. Fong, Brent M. Kuenzi, Nicole M. Mattson, John Lee, Kyle Sanchez, Ana Bojorquez-Gomez, Kyle Ford, Brenton P. Munson, Katherine Licon, Sarah Bergendahl, John Paul Shen, Jason F. Kreisberg, Prashant Mali, Jeffrey H. Hager, Michael A. White, Trey Ideker","doi":"10.1038/s41588-024-01971-9","DOIUrl":"https://doi.org/10.1038/s41588-024-01971-9","url":null,"abstract":"<p>Cancers are driven by alterations in diverse genes, creating dependencies that can be therapeutically targeted. However, many genetic dependencies have proven inconsistent across tumors. Here we describe SCHEMATIC, a strategy to identify a core network of highly penetrant, actionable genetic interactions. First, fundamental cellular processes are perturbed by systematic combinatorial knockouts across tumor lineages, identifying 1,805 synthetic lethal interactions (95% unreported). Interactions are then analyzed by hierarchical pooling, revealing that half segregate reliably by tissue type or biomarker status (51%) and a substantial minority are penetrant across lineages (34%). Interactions converge on 49 multigene systems, including MAPK signaling and BAF transcriptional regulatory complexes, which become essential on disruption of polymerases. Some 266 interactions translate to robust biomarkers of drug sensitivity, including frequent genetic alterations in the KDM5C/6A histone demethylases, which sensitize to inhibition of TIPARP (PARP7). SCHEMATIC offers a context-aware, data-driven approach to match genetic alterations to targeted therapies.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"168 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142665532","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: 10.1038/s41588-024-01977-3
NKX3.1-expressing intermediate Basal-B cells represent a transient basal stem cell state during prostate regeneration, inflammation and cancer initiation. Remarkably, activation of JAK/STAT signaling is essential in regulating expansion and differentiation of Basal-B-like cells during prostate inflammation, identifying this signaling pathway as a potential therapeutic target in prostatitis associated with increased Basal-B signature.
{"title":"Intermediate cells with activated JAK/STAT signaling in prostate regeneration and diseases","authors":"","doi":"10.1038/s41588-024-01977-3","DOIUrl":"10.1038/s41588-024-01977-3","url":null,"abstract":"NKX3.1-expressing intermediate Basal-B cells represent a transient basal stem cell state during prostate regeneration, inflammation and cancer initiation. Remarkably, activation of JAK/STAT signaling is essential in regulating expansion and differentiation of Basal-B-like cells during prostate inflammation, identifying this signaling pathway as a potential therapeutic target in prostatitis associated with increased Basal-B signature.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 12","pages":"2606-2607"},"PeriodicalIF":31.7,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142637043","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: 10.1038/s41588-024-01979-1
Wangxin Guo, Xiaoyu Zhang, Lin Li, Pengfei Shao, Chao Liang, Hongjiong Zhang, Kuo Liu, Shuoming Wang, Yunyi Peng, Jun Luo, Yi Ju, Angelo M. De Marzo, Chen Yu, Luonan Chen, Bin Zhou, Dong Gao
Unipotent basal and luminal stem cells maintain prostate homeostasis, with an intermediate cell population emerging during prostate inflammation or cancer. However, the identities of basal stem cell and intermediate cell population remain unclear. Here we identified a rare intermediate cell population expressing luminal markers (termed Basal-B) with enhanced organoid formation capacity, and a larger basal population (termed Basal-A). Genetic lineage tracing revealed Basal-B cells represented a transient basal stem cell state during prostate homeostasis and androgen-mediated regeneration. Activated JAK/STAT signaling was identified in Basal-B cells, and its inhibition significantly reduced Basal-B markers expression. Inflammation increased Basal-B-to-luminal cell transdifferentiation, but JAK/STAT inhibition notably attenuated this effect. Pten gene deletion increased Nkx3.1-expressing Basal-B-like cell population and led to neoplasia. In humans, h-Basal-B cells were more prevalent in benign prostate hyperplasia. This study reveals the identities of intermediate Basal-B cells and underscores the role of JAK/STAT signaling in prostate cell fate determination. This study identifies Basal-B cells as a transient cell state during prostate homeostasis and androgen-mediated regeneration. These cells exist in humans and increase in number with prostatitis and inflammation.
{"title":"JAK/STAT signaling maintains an intermediate cell population during prostate basal cell fate determination","authors":"Wangxin Guo, Xiaoyu Zhang, Lin Li, Pengfei Shao, Chao Liang, Hongjiong Zhang, Kuo Liu, Shuoming Wang, Yunyi Peng, Jun Luo, Yi Ju, Angelo M. De Marzo, Chen Yu, Luonan Chen, Bin Zhou, Dong Gao","doi":"10.1038/s41588-024-01979-1","DOIUrl":"10.1038/s41588-024-01979-1","url":null,"abstract":"Unipotent basal and luminal stem cells maintain prostate homeostasis, with an intermediate cell population emerging during prostate inflammation or cancer. However, the identities of basal stem cell and intermediate cell population remain unclear. Here we identified a rare intermediate cell population expressing luminal markers (termed Basal-B) with enhanced organoid formation capacity, and a larger basal population (termed Basal-A). Genetic lineage tracing revealed Basal-B cells represented a transient basal stem cell state during prostate homeostasis and androgen-mediated regeneration. Activated JAK/STAT signaling was identified in Basal-B cells, and its inhibition significantly reduced Basal-B markers expression. Inflammation increased Basal-B-to-luminal cell transdifferentiation, but JAK/STAT inhibition notably attenuated this effect. Pten gene deletion increased Nkx3.1-expressing Basal-B-like cell population and led to neoplasia. In humans, h-Basal-B cells were more prevalent in benign prostate hyperplasia. This study reveals the identities of intermediate Basal-B cells and underscores the role of JAK/STAT signaling in prostate cell fate determination. This study identifies Basal-B cells as a transient cell state during prostate homeostasis and androgen-mediated regeneration. These cells exist in humans and increase in number with prostatitis and inflammation.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 12","pages":"2776-2789"},"PeriodicalIF":31.7,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601020","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: 10.1038/s41588-024-01981-7
Jonas Koeppel, Juliane Weller, Thomas Vanderstichele, Leopold Parts
Structural variation, such as deletions, duplications, inversions and complex rearrangements, can have profound effects on gene expression, genome stability, phenotypic diversity and disease susceptibility. Structural variants can encompass up to millions of bases and have the potential to rearrange substantial segments of the genome. They contribute considerably more to genetic diversity in human populations and have larger effects on phenotypic traits than point mutations. Until recently, our understanding of the effects of structural variants was driven mainly by studying naturally occurring variation. New genome-engineering tools capable of generating deletions, insertions, inversions and translocations, together with the discovery of new recombinases and advances in creating synthetic DNA constructs, now enable the design and generation of an extended range of structural variation. Here, we discuss these tools and examples of their application and highlight existing challenges that will need to be overcome to fully harness their potential. Structural variations (SVs) impact gene expression, genome stability and disease susceptibility. This Review discusses recent advances in genome-engineering tools that enable precise SV generation and highlights the challenges that remain.
结构变异，如缺失、重复、倒位和复杂的重排，可对基因表达、基因组稳定性、表型多样性和疾病易感性产生深远影响。结构变异可包含多达数百万个碱基，并有可能重新排列基因组的大部分片段。与点突变相比，结构变异对人类群体遗传多样性的贡献更大，对表型特征的影响也更大。直到最近，我们对结构变异影响的了解还主要停留在对自然发生变异的研究上。新的基因组工程工具能够产生缺失、插入、倒位和易位，加上新重组酶的发现和合成 DNA 构建的进步，现在能够设计和产生更大范围的结构变异。在此，我们将讨论这些工具及其应用实例，并强调要充分利用这些工具的潜力需要克服的现有挑战。
{"title":"Engineering structural variants to interrogate genome function","authors":"Jonas Koeppel, Juliane Weller, Thomas Vanderstichele, Leopold Parts","doi":"10.1038/s41588-024-01981-7","DOIUrl":"10.1038/s41588-024-01981-7","url":null,"abstract":"Structural variation, such as deletions, duplications, inversions and complex rearrangements, can have profound effects on gene expression, genome stability, phenotypic diversity and disease susceptibility. Structural variants can encompass up to millions of bases and have the potential to rearrange substantial segments of the genome. They contribute considerably more to genetic diversity in human populations and have larger effects on phenotypic traits than point mutations. Until recently, our understanding of the effects of structural variants was driven mainly by studying naturally occurring variation. New genome-engineering tools capable of generating deletions, insertions, inversions and translocations, together with the discovery of new recombinases and advances in creating synthetic DNA constructs, now enable the design and generation of an extended range of structural variation. Here, we discuss these tools and examples of their application and highlight existing challenges that will need to be overcome to fully harness their potential. Structural variations (SVs) impact gene expression, genome stability and disease susceptibility. This Review discusses recent advances in genome-engineering tools that enable precise SV generation and highlights the challenges that remain.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 12","pages":"2623-2635"},"PeriodicalIF":31.7,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599616","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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