Cell genomicsPub Date : 2025-09-10Epub Date: 2025-07-03DOI: 10.1016/j.xgen.2025.100945
José Luis Cabrera-Alarcón, Marina Rosa-Moreno, Lucía Sánchez-García, Pablo Hernansanz-Agustín, Maria Concepción Jiménez-Gómez, Fernando Martínez, Fátima Sánchez-Cabo, José Antonio Enríquez
{"title":"Structural diversity and evolutionary constraints of oxidative phosphorylation.","authors":"José Luis Cabrera-Alarcón, Marina Rosa-Moreno, Lucía Sánchez-García, Pablo Hernansanz-Agustín, Maria Concepción Jiménez-Gómez, Fernando Martínez, Fátima Sánchez-Cabo, José Antonio Enríquez","doi":"10.1016/j.xgen.2025.100945","DOIUrl":"10.1016/j.xgen.2025.100945","url":null,"abstract":"<p><p>The oxidative phosphorylation (OxPhos) system is central to metabolism. The more than 90 structural subunits are encoded by different chromosome categories (autosomal, X, and mtDNA). The system is envisioned as an invariant structure between cells and individuals. However, a comprehensive analysis of the 1,000 Genomes Project data reveals unexpected genetic intra-individual variability resulting from the heterozygosity of diploid autosomal genes, while diversity at the population level is generated by variability in mtDNA. We characterized the different levels of structural constriction at evolutionary and population levels for all OxPhos protein residues. To support this analysis, we developed ConScore, a conservation-based predictor of variant impact within OxPhos proteins (area under the receiver operating characteristic curve [ROC-AUC] = 0.97; area under the precision-recall curve [PR-AUC] = 0.94). Notably, for the nuclear-encoded subunits, we found mechanisms limiting individual variability as allelic imbalance or homozygosity bias. Integrating structural, functional, and genetic data, we highlight the significance of each OxPhos protein position, expanding insights into its role in speciation and disease.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":" ","pages":"100945"},"PeriodicalIF":11.1,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144565492","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell genomicsPub Date : 2025-09-10Epub Date: 2025-07-24DOI: 10.1016/j.xgen.2025.100954
Zishuai Wang, Zixin Li, Tao Huang, Jianhai Chen, Pan Xu, Ruimin Qiao, Hongwei Yin, Chengyi Song, Dongjie Zhang, Di Liu, Shuhong Zhao, Martien A M Groenen, Ole Madsen, Yanlin Zhang, Lijing Bai, Kui Li
{"title":"Genomic insights into the demographic history and local adaptation of wild boars across Eurasia.","authors":"Zishuai Wang, Zixin Li, Tao Huang, Jianhai Chen, Pan Xu, Ruimin Qiao, Hongwei Yin, Chengyi Song, Dongjie Zhang, Di Liu, Shuhong Zhao, Martien A M Groenen, Ole Madsen, Yanlin Zhang, Lijing Bai, Kui Li","doi":"10.1016/j.xgen.2025.100954","DOIUrl":"10.1016/j.xgen.2025.100954","url":null,"abstract":"<p><p>Wild boars exhibit genetic and phenotypic diversity shaped by migrations and local adaptations. Their expansion across Eurasia, especially in Central Asia, remains underexplored. Here, we present newly sequenced whole-genome data of 47 wild boars from Eastern Asia, Central Asia, and Europe, combined with 49 existing genomes, creating a comprehensive dataset of 96 individuals. Our analyses show that Asian wild boars and Southeast Asian Suids split ∼3.6 million years ago (mya), with Central Asian and Southern Chinese ancestors diverging ∼1.8 mya. The split between Central Asian and European-Near East ancestors occurred ∼0.9 mya, followed by a European-Near East divergence ∼0.6 mya. We identify signatures of local adaptation in Central Asian populations, including two positively selected variants in LPIN1, associated with lipid metabolism, and a missense mutation in ALPK2, linked to meat traits. These findings provide insights into wild boar dispersal and adaptation and shed light on domestic pig breeding.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":" ","pages":"100954"},"PeriodicalIF":11.1,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144719235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell genomicsPub Date : 2025-09-10Epub Date: 2025-07-03DOI: 10.1016/j.xgen.2025.100929
David C Goldberg, Cameron Cloud, Sol Moe Lee, Bret Barnes, Steven Gruber, Elliot Kim, Anita Pottekat, Maximillian S Westphal, Luana McAuliffe, Elisa Majounie, Manesh Kalayil Manian, Qingdi Zhu, Christine Tran, Mark Hansen, Jelena Stojakovic, Jared B Parker, Rahul M Kohli, Rishi Porecha, Nicole Renke, Wanding Zhou
{"title":"Scalable screening of ternary-code DNA methylation dynamics associated with human traits.","authors":"David C Goldberg, Cameron Cloud, Sol Moe Lee, Bret Barnes, Steven Gruber, Elliot Kim, Anita Pottekat, Maximillian S Westphal, Luana McAuliffe, Elisa Majounie, Manesh Kalayil Manian, Qingdi Zhu, Christine Tran, Mark Hansen, Jelena Stojakovic, Jared B Parker, Rahul M Kohli, Rishi Porecha, Nicole Renke, Wanding Zhou","doi":"10.1016/j.xgen.2025.100929","DOIUrl":"10.1016/j.xgen.2025.100929","url":null,"abstract":"<p><p>Epigenome-wide association studies (EWASs) are transforming our understanding of the interplay between epigenetics and complex human traits. We introduce the methylation screening array (MSA) to enable scalable and quantitative screening of trait-associated DNA cytosine modifications in large human populations. The MSA integrates EWASs and cell-type-linked methylation signatures, covering diverse traits and diseases. Using the MSA to profile the ternary-code DNA methylations-dissecting 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC), and unmodified cytosine-revealed a previously unappreciated role of 5hmC in mediating human trait associations and epigenetic clocks. We demonstrated that 5hmCs complement 5mCs in defining epigenetic cell identities. In-depth analyses highlighted the cell-type context of EWAS and genome-wide association study (GWAS) hits. Targeting aging, we uncovered shared and tissue-specific 5hmC aging dynamics and tissue-specific rates of mitotic hyper- and hypomethylation. These findings chart a landscape of the complex interplay of the two forms of cytosine modifications in diverse human tissues and their roles in health and disease.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":" ","pages":"100929"},"PeriodicalIF":11.1,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144565491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell genomicsPub Date : 2025-09-10Epub Date: 2025-07-18DOI: 10.1016/j.xgen.2025.100951
Wenjing Wang, Wei Lin Liew, Shiqi Huang, Edmund Chan, Amelia Li Min Tan, Chi Tian, Yihan Tong, Yuntian Zhang, Fei Liu, Yixian Qin, Sean Jun Leong Ou, Suresh Anand Sadananthan, Sambasivam Sendhil Velan, Kavita Venkataraman, Sarah R Langley, Petretto Enrico, Shawn Hoon, Kwang Wei Tham, Yap Seng Chong, Yung Seng Lee, Melvin Khee-Shing Leow, Xueling Sim, Chin Meng Khoo, E Shyong Tai, Eric Yin Hao Khoo, Mei Hui Liu, Boxiang Liu
{"title":"Impact of polymorphisms on gene expression and splicing in response to exercise and diet-induced weight loss in human skeletal muscle tissues.","authors":"Wenjing Wang, Wei Lin Liew, Shiqi Huang, Edmund Chan, Amelia Li Min Tan, Chi Tian, Yihan Tong, Yuntian Zhang, Fei Liu, Yixian Qin, Sean Jun Leong Ou, Suresh Anand Sadananthan, Sambasivam Sendhil Velan, Kavita Venkataraman, Sarah R Langley, Petretto Enrico, Shawn Hoon, Kwang Wei Tham, Yap Seng Chong, Yung Seng Lee, Melvin Khee-Shing Leow, Xueling Sim, Chin Meng Khoo, E Shyong Tai, Eric Yin Hao Khoo, Mei Hui Liu, Boxiang Liu","doi":"10.1016/j.xgen.2025.100951","DOIUrl":"10.1016/j.xgen.2025.100951","url":null,"abstract":"<p><p>Weight loss through exercise and diet reduces the risk of type 2 diabetes, but the genetic regulation of gene expression and splicing in response to weight loss remains unclear in humans. We collected clinical data and skeletal muscle biopsies from 54 overweight/obese Asian individuals before and after a 16-week lifestyle intervention, which resulted in an average of ∼10% weight loss, accompanied by an ∼30% increase in insulin-stimulated glucose uptake. Improvements were observed in 118 of 252 clinical traits and six blood lipids. Transcriptomic analysis of paired skeletal muscle biopsies identified 505 differentially expressed genes enriched in mitochondrial function and insulin sensitivity. Thousands of muscle-specific expression/splicing quantitative trait loci (e/sQTLs) were detected pre- and post-intervention, including hundreds of lifestyle-responsive e/sQTLs. Notably, approximately 4.2% of eQTLs and 7.3% of sQTLs showed Asian specificity. Joint analysis with genome-wide association study (GWAS) identified 16 putative metabolic risk genes. Our study reveals gene-by-lifestyle interactions and how lifestyle modulates gene regulation in skeletal muscle.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":" ","pages":"100951"},"PeriodicalIF":11.1,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144669103","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell genomicsPub Date : 2025-09-10Epub Date: 2025-07-17DOI: 10.1016/j.xgen.2025.100928
Chunfu Xiao, Xiaoge Liu, Peiyu Liu, Xinwei Xu, Chao Yao, Chunqiong Li, Qi Xiao, Tiannan Guo, Li Zhang, Yongjun Qian, Chao Wang, Yiting Dong, Yingxuan Wang, Zhi Peng, Chuanhui Han, Qiang Cheng, Ni A An, Chuan-Yun Li
{"title":"Oncogenic roles of young human de novo genes and their potential as neoantigens in cancer immunotherapy.","authors":"Chunfu Xiao, Xiaoge Liu, Peiyu Liu, Xinwei Xu, Chao Yao, Chunqiong Li, Qi Xiao, Tiannan Guo, Li Zhang, Yongjun Qian, Chao Wang, Yiting Dong, Yingxuan Wang, Zhi Peng, Chuanhui Han, Qiang Cheng, Ni A An, Chuan-Yun Li","doi":"10.1016/j.xgen.2025.100928","DOIUrl":"10.1016/j.xgen.2025.100928","url":null,"abstract":"<p><p>Young human de novo genes, recently emerging from non-coding regions, are expected to contribute to human-specific traits and diseases. However, systematic explorations of this connection have been lacking. Here, we report 37 recently originated de novo genes in humans, with their evolution and characteristics defined within an updated genomic context. The expression of these genes is significantly upregulated and temporospatially expanded in tumors, partially associated with extrachromosomal DNA amplification. Depletion of 57.1% of these genes suppresses tumor cell proliferation, underscoring their roles in tumorigenesis. As a proof of concept, we developed mRNA vaccines expressing ELFN1-AS1 and TYMSOS-young genes specifically expressed during early development but reactivated exclusively in tumors. In humanized mice, these vaccines triggered specific T cell activation and inhibited tumor growth. The antigens derived from these genes are immunogenic and capable of eliciting antigen-specific T cell activation in colorectal cancer patients. These findings underscore young human de novo genes as neoantigens in cancer immunotherapy.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":" ","pages":"100928"},"PeriodicalIF":11.1,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144669104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell genomicsPub Date : 2025-09-09DOI: 10.1016/j.xgen.2025.100985
Sebastian Palacios, Simone Bruno, Ron Weiss, Elia Salibi, Isabella Goodchild-Michelman, Andrew Kane, Katherine Ilia, Domitilla Del Vecchio
{"title":"Analog epigenetic memory revealed by targeted chromatin editing.","authors":"Sebastian Palacios, Simone Bruno, Ron Weiss, Elia Salibi, Isabella Goodchild-Michelman, Andrew Kane, Katherine Ilia, Domitilla Del Vecchio","doi":"10.1016/j.xgen.2025.100985","DOIUrl":"https://doi.org/10.1016/j.xgen.2025.100985","url":null,"abstract":"<p><p>Cells store information by means of chromatin modifications that persist through cell divisions and can hold gene expression silenced over generations. However, how these modifications may maintain other gene expression states has remained unclear. This study shows that chromatin modifications can maintain a wide range of gene expression levels over time, thus uncovering analog epigenetic memory. By engineering a genomic reporter and epigenetic effectors, we tracked the gene expression dynamics following targeted perturbations to the chromatin state. We found that distinct grades of DNA methylation led to corresponding, persistent gene expression levels. Altering the DNA methylation grade, in turn, resulted in permanent loss of gene expression memory. Consistent with experiments, our chromatin modification model indicates that analog memory arises when the positive feedback between DNA methylation and repressive histone modifications is lacking. This discovery will lead to a deeper understanding of epigenetic memory and to new tools for synthetic biology.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":" ","pages":"100985"},"PeriodicalIF":11.1,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145034782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell genomicsPub Date : 2025-09-09DOI: 10.1016/j.xgen.2025.100981
Taylor N LaFlam, Christian B Billesbølle, Tuan Dinh, Finn D Wolfreys, Erick Lu, Tomas Matteson, Jinping An, Ying Xu, Arushi Singhal, Nadav Brandes, Vasilis Ntranos, Aashish Manglik, Jason G Cyster, Chun Jimmie Ye
{"title":"Phenotypic pleiotropy of missense variants in human B cell confinement receptor P2RY8.","authors":"Taylor N LaFlam, Christian B Billesbølle, Tuan Dinh, Finn D Wolfreys, Erick Lu, Tomas Matteson, Jinping An, Ying Xu, Arushi Singhal, Nadav Brandes, Vasilis Ntranos, Aashish Manglik, Jason G Cyster, Chun Jimmie Ye","doi":"10.1016/j.xgen.2025.100981","DOIUrl":"10.1016/j.xgen.2025.100981","url":null,"abstract":"<p><p>Missense variants can have pleiotropic effects on protein function, and predicting these effects can be difficult. We performed near-saturation deep mutational scanning of P2RY8, a G protein-coupled receptor that promotes germinal center B cell confinement. We assayed the effect of each variant on surface expression, migration, and proliferation. We delineated variants that affected both expression and function, affected function independently of expression, and discrepantly affected migration and proliferation. We also used cryo-electron microscopy to determine the structure of activated, ligand-bound P2RY8, providing structural insights into the effects of variants on ligand binding and signal transmission. We applied the deep mutational scanning results to both improve computational variant effect predictions and to characterize the phenotype of germline variants and lymphoma-associated variants. Together, our results demonstrate the power of integrating deep mutational scanning, structure determination, and in silico prediction to advance the understanding of a receptor important in human health.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":" ","pages":"100981"},"PeriodicalIF":11.1,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145034846","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell genomicsPub Date : 2025-09-09DOI: 10.1016/j.xgen.2025.100987
Heather A Parsons, Conor Messer, Katheryn Santos, Jakob Weiss, David Merrell, Brian P Danysh, Melissa E Hughes, Gregory J Kirkner, Ashka Patel, Julian Hess, Kerry Sendrick, Chip Stewart, Elizabeth Grant, Kristy Schlueter-Kuck, Albert Grinshpun, Nikhil Wagle, Jamunarani Veeraraghavan, Jose Pablo Leone, Rachel A Freedman, Otto Metzger, Rachel Schiff, Eric P Winer, Sara M Tolaney, Mothaffar Rimawi, Ian E Krop, Gad Getz, Nancy U Lin
{"title":"Detection of heterogeneous resistance mechanisms to tyrosine kinase inhibitors from cell-free DNA.","authors":"Heather A Parsons, Conor Messer, Katheryn Santos, Jakob Weiss, David Merrell, Brian P Danysh, Melissa E Hughes, Gregory J Kirkner, Ashka Patel, Julian Hess, Kerry Sendrick, Chip Stewart, Elizabeth Grant, Kristy Schlueter-Kuck, Albert Grinshpun, Nikhil Wagle, Jamunarani Veeraraghavan, Jose Pablo Leone, Rachel A Freedman, Otto Metzger, Rachel Schiff, Eric P Winer, Sara M Tolaney, Mothaffar Rimawi, Ian E Krop, Gad Getz, Nancy U Lin","doi":"10.1016/j.xgen.2025.100987","DOIUrl":"https://doi.org/10.1016/j.xgen.2025.100987","url":null,"abstract":"<p><p>Though there has been substantial progress in the development of anti-human epidermal growth factor receptor 2 (HER2) therapies to treat HER2-positive metastatic breast cancer (MBC) within the past two decades, most patients still experience disease progression and cancer-related death. HER2-directed tyrosine kinase inhibitors can be highly effective therapies for patients with HER2-positive MBC; however, an understanding of resistance mechanisms is needed to better inform treatment approaches. We performed whole-exome sequencing on 111 patients with 73 tumor biopsies and 120 cell-free DNA samples to assess mechanisms of resistance. In 11 of 26 patients with acquired resistance, we identified alterations in previously characterized genes, such as PIK3CA and ERBB2, that could explain treatment resistance. Mutations in growing subclones identified potential mechanisms of resistance in 5 of 26 patients and included alterations in ESR1, FGFR2, and FGFR4. Additional studies are needed to assess the functional role and clinical utility of these alterations in driving resistance.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":" ","pages":"100987"},"PeriodicalIF":11.1,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145034833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell genomicsPub Date : 2025-09-09DOI: 10.1016/j.xgen.2025.100988
Ann Lin, Kaitlyn Spees, Raeline Valbuena, Jakob Wirbel, Aravind Natarajan, Nora Enright, Ami S Bhatt, Michael C Bassik
{"title":"A peptide display system identifies a potent mutant β-melanocyte-stimulating hormone agonist of melanocortin-4 receptor.","authors":"Ann Lin, Kaitlyn Spees, Raeline Valbuena, Jakob Wirbel, Aravind Natarajan, Nora Enright, Ami S Bhatt, Michael C Bassik","doi":"10.1016/j.xgen.2025.100988","DOIUrl":"https://doi.org/10.1016/j.xgen.2025.100988","url":null,"abstract":"<p><p>Non-olfactory G-protein-coupled receptors (GPCRs) regulate vital physiological functions and are targets for ∼34% of US Food and Drug Administration (FDA)-approved drugs. While small-molecule-activated GPCRs are well studied, there is growing interest in peptide GPCRs, particularly the melanocortin-4 receptor (MC4R), a key regulator of energy balance and appetite. Activation of MC4R by β-melanocyte-stimulating hormone (β-MSH) reduces food intake, and pathway dysfunction leads to obesity. However, current methods to study GPCR-peptide interactions are resource intensive and low throughput. To address this, we developed a high-throughput cell surface peptide display platform with a β-arrestin-based MC4R reporter to screen over 2,000 β-MSH point mutants. This approach identified peptide variants that significantly impact MC4R activation, including a novel D5H mutant with enhanced receptor activation. Our results demonstrate a scalable method to directly link GPCR activation to peptide variants, offering insights for therapeutic peptide design.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":" ","pages":"100988"},"PeriodicalIF":11.1,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145034772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell genomicsPub Date : 2025-09-03DOI: 10.1016/j.xgen.2025.100984
Dubravka Vučićević, Che-Wei Hsu, Lorena Sofia Lopez Zepeda, Martin Burkert, Antje Hirsekorn, Ilija Bilić, Nicolai Kastelić, Markus Landthaler, Scott Allen Lacadie, Uwe Ohler
{"title":"Sensitive dissection of a genomic regulatory landscape using bulk and targeted single-cell activation.","authors":"Dubravka Vučićević, Che-Wei Hsu, Lorena Sofia Lopez Zepeda, Martin Burkert, Antje Hirsekorn, Ilija Bilić, Nicolai Kastelić, Markus Landthaler, Scott Allen Lacadie, Uwe Ohler","doi":"10.1016/j.xgen.2025.100984","DOIUrl":"https://doi.org/10.1016/j.xgen.2025.100984","url":null,"abstract":"<p><p>Enhancers are known to spatiotemporally regulate gene transcription, yet the identification of enhancers and their target genes is often indirect, low resolution, and/or assumptive. To identify and functionally perturb enhancers at their endogenous sites, we performed a pooled tiling CRISPR activation (CRISPRa) screen surrounding PHOX2B, a master regulator of neuronal cell fate and a key player in neuroblastoma, and found many CRISPRa-responsive elements (CaREs) that alter cellular growth. To determine CaRE target genes, we developed TESLA-seq (targeted single-cell activation), which combines CRISPRa screening with targeted single-cell RNA sequencing and enables the parallel readout of the effect of hundreds of enhancers on all genes in the locus. While most TESLA-revealed CaRE-gene relationships involved neuroblastoma-related regulatory elements, we found many CaREs and target connections normally active only in other tissues. This highlights the power of TESLA-seq to reveal gene regulatory networks, including edges active outside of a given experimental system.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":" ","pages":"100984"},"PeriodicalIF":11.1,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145034883","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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