Genome Biology最新文献

{"title":"Functional screening reveals genetic dependencies and diverging cell cycle control in atypical teratoid rhabdoid tumors","authors":"Daniel J. Merk, Foteini Tsiami, Sophie Hirsch, Bianca Walter, Lara A. Haeusser, Jens D. Maile, Aaron Stahl, Mohamed A. Jarboui, Anna Lechado-Terradas, Franziska Klose, Sepideh Babaei, Jakob Admard, Nicolas Casadei, Cristiana Roggia, Michael Spohn, Jens Schittenhelm, Stephan Singer, Ulrich Schüller, Federica Piccioni, Nicole S. Persky, Manfred Claassen, Marcos Tatagiba, Philipp J. Kahle, David E. Root, Markus Templin, Ghazaleh Tabatabai","doi":"10.1186/s13059-024-03438-w","DOIUrl":"https://doi.org/10.1186/s13059-024-03438-w","url":null,"abstract":"Atypical teratoid rhabdoid tumors (ATRT) are incurable high-grade pediatric brain tumors. Despite intensive research efforts, the prognosis for ATRT patients under currently established treatment protocols is poor. While novel therapeutic strategies are urgently needed, the generation of molecular-driven treatment concepts is a challenge mainly due to the absence of actionable genetic alterations. We here use a functional genomics approach to identify genetic dependencies in ATRT, validate selected hits using a functionally instructed small molecule drug library, and observe preferential activity in ATRT cells without subgroup-specific selectivity. CDK4/6 inhibitors are among the most potent drugs and display anti-tumor efficacy due to mutual exclusive dependency on CDK4 or CDK6. Chemogenetic interactor screens reveal a broad spectrum of G1 phase cell cycle regulators that differentially enable cell cycle progression and modulate response to CDK4/6 inhibition in ATRT cells. In this regard, we find that the ubiquitin ligase substrate receptor AMBRA1 acts as a context-specific inhibitor of cell cycle progression by regulating key components of mitosis including aurora kinases. Our data provide a comprehensive resource of genetic and chemical dependencies in ATRTs, which will inform further preclinical evaluation of novel targeted therapies for this tumor entity. Furthermore, this study reveals a unique mechanism of cell cycle inhibition as the basis for tumor suppressive functions of AMBRA1.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"79 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142758451","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":"MoCHI: neural networks to fit interpretable models and quantify energies, energetic couplings, epistasis, and allostery from deep mutational scanning data","authors":"Andre J. Faure, Ben Lehner","doi":"10.1186/s13059-024-03444-y","DOIUrl":"https://doi.org/10.1186/s13059-024-03444-y","url":null,"abstract":"We present MoCHI, a tool to fit interpretable models using deep mutational scanning data. MoCHI infers free energy changes, as well as interaction terms (energetic couplings) for specified biophysical models, including from multimodal phenotypic data. When a user-specified model is unavailable, global nonlinearities (epistasis) can be estimated from the data. MoCHI also leverages ensemble, background-averaged epistasis to learn sparse models that can incorporate higher-order epistatic terms. MoCHI is freely available as a Python package ( https://github.com/lehner-lab/MoCHI ) relying on the PyTorch machine learning framework and allows biophysical measurements at scale, including the construction of allosteric maps of proteins.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"26 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142758455","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":"SMART: spatial transcriptomics deconvolution using marker-gene-assisted topic model","authors":"Chen Xi Yang, Don D. Sin, Raymond T. Ng","doi":"10.1186/s13059-024-03441-1","DOIUrl":"https://doi.org/10.1186/s13059-024-03441-1","url":null,"abstract":"While spatial transcriptomics offer valuable insights into gene expression patterns within the spatial context of tissue, many technologies do not have a single-cell resolution. Here, we present SMART, a marker gene-assisted deconvolution method that simultaneously infers the cell type-specific gene expression profile and the cellular composition at each spot. Using multiple datasets, we show that SMART outperforms the existing methods in realistic settings. It also provides a two-stage approach to enhance its performance on cell subtypes. The covariate model of SMART enables the identification of cell type-specific differentially expressed genes across conditions, elucidating biological changes at a single-cell-type resolution.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"82 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142758506","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":"HTAD: a human-in-the-loop framework for supervised chromatin domain detection","authors":"Wei Shen, Ping Zhang, Yiwei Jiang, Hailin Tao, Zhike Zi, Li Li","doi":"10.1186/s13059-024-03445-x","DOIUrl":"https://doi.org/10.1186/s13059-024-03445-x","url":null,"abstract":"Topologically associating domains (TADs) are essential units of genome architecture, influencing transcriptional regulation and diseases. Despite numerous methods proposed for TAD identification, it remains challenging due to complex background and nested TAD structures. We introduce HTAD, a human-in-the-loop TAD caller that combines machine learning with human supervision to achieve high accuracy. HTAD begins with feature extraction for potential TAD border pairs, followed by an interactive labeling process through active learning. Performance assessments using public curation and synthetic datasets demonstrate HTAD’s superiority over other state-of-the-art methods and reveal highly hierarchical TAD structures, offering a human-in-the-loop solution for detecting complex genomic patterns.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"49 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142758168","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":"Hierarchical annotation of eQTLs by H-eQTL enables identification of genes with cell type-divergent regulation","authors":"Pawel F. Przytycki, Katherine S. Pollard","doi":"10.1186/s13059-024-03440-2","DOIUrl":"https://doi.org/10.1186/s13059-024-03440-2","url":null,"abstract":"While context-type-specific regulation of genes is largely determined by cis-regulatory regions, attempts to identify cell type-specific eQTLs are complicated by the nested nature of cell types. We present hierarchical eQTL (H-eQTL), a network-based model for hierarchical annotation of bulk-derived eQTLs to levels of a cell type tree using single-cell chromatin accessibility data and no clustering of cells into discrete cell types. Using our model, we annotate bulk-derived eQTLs from the developing brain with high specificity to levels of a cell type hierarchy, which allows sensitive detection of genes with multiple distinct non-coding elements regulating their expression in different cell types.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"256 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142697031","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":"Publisher Correction: Tagging large CNV blocks in wheat boosts digitalization of germplasm resources by ultra-low-coverage sequencing","authors":"Jianxia Niu, Wenxi Wang, Zihao Wang, Zhe Chen, Xiaoyu Zhang, Zhen Qin, Lingfeng Miao, Zhengzhao Yang, Chaojie Xie, Mingming Xin, Huiru Peng, Yingyin Yao, Jie Liu, Zhongfu Ni, Qixin Sun, Weilong Guo","doi":"10.1186/s13059-024-03442-0","DOIUrl":"https://doi.org/10.1186/s13059-024-03442-0","url":null,"abstract":"<p><b>Correction</b><b>: </b><b>Genome Biol 25, 171 (2024)</b></p><p><b>https://doi.org/10.1186/s13059-024-03315-6</b></p><br/><p>Following publication of the original article [1], the authors identified a typesetting error, whereby the equal contribution statement was mistakenly omitted. The correct statement is as follow: Jianxia Niu, Wenxi Wang and Zihao Wang are co-first authors and contributed equally.</p><p>The original article [1] has been corrected.</p><ol data-track-component=\"outbound reference\" data-track-context=\"references section\"><li data-counter=\"1.\"><p>Niu J, Wang W, Wang Z, et al. Tagging large CNV blocks in wheat boosts digitalization of germplasm resources by ultra-low-coverage sequencing. Genome Biol. 2024;25:171. https://doi.org/10.1186/s13059-024-03315-6.</p><p>Article CAS PubMed PubMed Central Google Scholar </p></li></ol><p>Download references<svg aria-hidden=\"true\" focusable=\"false\" height=\"16\" role=\"img\" width=\"16\"><use xlink:href=\"#icon-eds-i-download-medium\" xmlns:xlink=\"http://www.w3.org/1999/xlink\"></use></svg></p><span>Author notes</span><ol><li><p>Jianxia Niu, Wenxi Wang and Zihao Wang are co-first authors and contributed equally.</p></li></ol><h3>Authors and Affiliations</h3><ol><li><p>Frontiers Science Center for Molecular Design Breeding, Key Laboratory of Crop Heterosis and Utilization, Beijing Key Laboratory of Crop Genetic Improvement, China Agricultural University, Beijing, 100193, China</p><p>Jianxia Niu, Wenxi Wang, Zihao Wang, Zhe Chen, Xiaoyu Zhang, Zhen Qin, Lingfeng Miao, Zhengzhao Yang, Chaojie Xie, Mingming Xin, Huiru Peng, Yingyin Yao, Jie Liu, Zhongfu Ni, Qixin Sun & Weilong Guo</p></li><li><p>Sanya Institute of China Agricultural University, Sanya, 572025, China</p><p>Jianxia Niu & Zihao Wang</p></li></ol><span>Authors</span><ol><li><span>Jianxia Niu</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Wenxi Wang</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Zihao Wang</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Zhe Chen</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Xiaoyu Zhang</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Zhen Qin</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Lingfeng Miao</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Zhengzhao Yang</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"3 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142697050","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 genomic portrait of the Picene culture provides new insights into the Italic Iron Age and the legacy of the Roman Empire in Central Italy","authors":"Francesco Ravasini, Helja Kabral, Anu Solnik, Luciana de Gennaro, Francesco Montinaro, Ruoyun Hui, Chiara Delpino, Stefano Finocchi, Pierluigi Giroldini, Oscar Mei, Michael Allen Beck De Lotto, Elisabetta Cilli, Mogge Hajiesmaeil, Letizia Pistacchia, Flavia Risi, Chiara Giacometti, Christiana Lyn Scheib, Kristiina Tambets, Mait Metspalu, Fulvio Cruciani, Eugenia D’Atanasio, Beniamino Trombetta","doi":"10.1186/s13059-024-03430-4","DOIUrl":"https://doi.org/10.1186/s13059-024-03430-4","url":null,"abstract":"The Italic Iron Age is characterized by the presence of various ethnic groups partially examined from a genomic perspective. To explore the evolution of Iron Age Italic populations and the genetic impact of Romanization, we focus on the Picenes, one of the most fascinating pre-Roman civilizations, who flourished on the Middle Adriatic side of Central Italy between the 9th and the 3rd century BCE, until the Roman colonization. More than 50 samples are reported, spanning more than 1000 years of history from the Iron Age to Late Antiquity. Despite cultural diversity, our analysis reveals no major differences between the Picenes and other coeval populations, suggesting a shared genetic history of the Central Italian Iron Age ethnic groups. Nevertheless, a slight genetic differentiation between populations along the Adriatic and Tyrrhenian coasts can be observed, possibly due to different population dynamics in the two sides of Italy and/or genetic contacts across the Adriatic Sea. Additionally, we identify several individuals with ancestries deviating from their general population. Lastly, in our Late Antiquity site, we observe a drastic change in the genetic landscape of the Middle Adriatic region, indicating a relevant influx from the Near East, possibly as a consequence of Romanization. Our findings, consistently with archeological hypotheses, suggest genetic interactions across the Adriatic Sea during the Bronze/Iron Age and a high level of individual mobility typical of cosmopolitan societies. Finally, we highlight the role of the Roman Empire in shaping genetic and phenotypic changes that greatly impact the Italian peninsula.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"81 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142678276","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":"scStateDynamics: deciphering the drug-responsive tumor cell state dynamics by modeling single-cell level expression changes","authors":"Wenbo Guo, Xinqi Li, Dongfang Wang, Nan Yan, Qifan Hu, Fan Yang, Xuegong Zhang, Jianhua Yao, Jin Gu","doi":"10.1186/s13059-024-03436-y","DOIUrl":"https://doi.org/10.1186/s13059-024-03436-y","url":null,"abstract":"Understanding tumor cell heterogeneity and plasticity is crucial for overcoming drug resistance. Single-cell technologies enable analyzing cell states at a given condition, but catenating static cell snapshots to characterize dynamic drug responses remains challenging. Here, we propose scStateDynamics, an algorithm to infer tumor cell state dynamics and identify common drug effects by modeling single-cell level gene expression changes. Its reliability is validated on both simulated and lineage tracing data. Application to real tumor drug treatment datasets identifies more subtle cell subclusters with different drug responses beyond static transcriptome similarity and disentangles drug action mechanisms from the cell-level expression changes.\u0000","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"19 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142678435","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":"Considerations in the search for epistasis","authors":"Marleen Balvert, Johnathan Cooper-Knock, Julian Stamp, Ross P. Byrne, Soufiane Mourragui, Juami van Gils, Stefania Benonisdottir, Johannes Schlüter, Kevin Kenna, Sanne Abeln, Alfredo Iacoangeli, Joséphine T. Daub, Brian L. Browning, Gizem Taş, Jiajing Hu, Yan Wang, Elham Alhathli, Calum Harvey, Luna Pianesi, Sara C. Schulte, Jorge González-Domínguez, Erik Garrisson, Michael P. Snyder, Alexander Schönhuth, Letitia M. F. Sng, Natalie A. Twine","doi":"10.1186/s13059-024-03427-z","DOIUrl":"https://doi.org/10.1186/s13059-024-03427-z","url":null,"abstract":"Epistasis refers to changes in the effect on phenotype of a unit of genetic information, such as a single nucleotide polymorphism or a gene, dependent on the context of other genetic units. Such interactions are both biologically plausible and good candidates to explain observations which are not fully explained by an additive heritability model. However, the search for epistasis has so far largely failed to recover this missing heritability. We identify key challenges and propose that future works need to leverage idealized systems, known biology and even previously identified epistatic interactions, in order to guide the search for new interactions.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"11 1","pages":""},"PeriodicalIF":12.3,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142671019","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":"Transcription of a centromere-enriched retroelement and local retention of its RNA are significant features of the CENP-A chromatin landscape.","authors":"B J Chabot, R Sun, A Amjad, S J Hoyt, L Ouyang, C Courret, R Drennan, L Leo, A M Larracuente, L J Core, R J O'Neill, B G Mellone","doi":"10.1186/s13059-024-03433-1","DOIUrl":"10.1186/s13059-024-03433-1","url":null,"abstract":"<p><strong>Background: </strong>Centromeres depend on chromatin containing the conserved histone H3 variant CENP-A for function and inheritance, while the role of centromeric DNA repeats remains unclear. Retroelements are prevalent at centromeres across taxa and represent a potential mechanism for promoting transcription to aid in CENP-A incorporation or for generating RNA transcripts to maintain centromere integrity.</p><p><strong>Results: </strong>In this study, we probe into the transcription and RNA localization of the centromere-enriched retroelement G2/Jockey-3 (hereafter referred to as Jockey-3) in Drosophila melanogaster, currently the only in vivo model with assembled centromeres. We find that Jockey-3 is a major component of the centromeric transcriptome and produces RNAs that localize to centromeres in metaphase. Leveraging the polymorphism of Jockey-3 and a de novo centromere system, we show that these RNAs remain associated with their cognate DNA sequences in cis, suggesting they are unlikely to perform a sequence-specific function at all centromeres. We show that Jockey-3 transcription is positively correlated with the presence of CENP-A and that recent Jockey-3 transposition events have occurred preferentially at CENP-A-containing chromatin.</p><p><strong>Conclusions: </strong>We propose that Jockey-3 preferentially inserts at the centromere to ensure its own selfish propagation, while contributing to transcription across these regions. Given the conservation of retroelements as centromere components through evolution, our findings may offer a basis for understanding similar associations in other species.</p>","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":"25 1","pages":"295"},"PeriodicalIF":10.1,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11575011/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667596","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}