Cell genomicsPub Date : 2025-10-02DOI: 10.1016/j.xgen.2025.101031
Tamara A Potapova, Paxton Kostos, Sean McKinney, Matthew Borchers, Jeff Haug, Andrea Guarracino, Steven J Solar, Mark Mattingly, Graciela Monfort Anez, Leonardo Gomes de Lima, Yan Wang, Chongbei Zhao, Kate Hall, Madelaine Gogol, Sophie Hoffman, Dmitry Antipov, Arang Rhie, Monika Cechova, Karen H Miga, Erik Garrison, Adam M Phillippy, Jennifer L Gerton
{"title":"Chromosome-specific epigenetic control and transmission of ribosomal DNA arrays in Hominidae genomes.","authors":"Tamara A Potapova, Paxton Kostos, Sean McKinney, Matthew Borchers, Jeff Haug, Andrea Guarracino, Steven J Solar, Mark Mattingly, Graciela Monfort Anez, Leonardo Gomes de Lima, Yan Wang, Chongbei Zhao, Kate Hall, Madelaine Gogol, Sophie Hoffman, Dmitry Antipov, Arang Rhie, Monika Cechova, Karen H Miga, Erik Garrison, Adam M Phillippy, Jennifer L Gerton","doi":"10.1016/j.xgen.2025.101031","DOIUrl":"https://doi.org/10.1016/j.xgen.2025.101031","url":null,"abstract":"<p><p>Ribosomal RNA (rRNA) genes are organized in tandem arrays known as ribosomal DNA (rDNA) on multiple chromosomes in Hominidae genomes. We measured copy number and transcriptional activity status of rRNA gene arrays across multiple individual genomes, revealing an identifiable fingerprint of rDNA copy number and activity. In some cases, entire arrays were transcriptionally silent, characterized by high DNA methylation across the rRNA gene, inaccessible chromatin, and the absence of transcription factors and transcripts. Silent arrays showed reduced association with the nucleolus and decreased interchromosomal interactions, consistent with the model that nucleolar organizer function depends on transcriptional activity. Removing rDNA methylation activated silent arrays. Array activity status remained stable through induced pluripotent stem cell reprogramming and differentiation into cerebral and intestinal organoids. Haplotype tracing in two unrelated family trios showed paternal transmission of silent arrays. We propose that the epigenetic state buffers rRNA gene dosage, specifies nucleolar organizer function, and can propagate transgenerationally.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":" ","pages":"101031"},"PeriodicalIF":11.1,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145226383","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 : 2025-10-02DOI: 10.1016/j.xgen.2025.101032
Jie Xiong, Xiaoting Zhu, Yutong Guo, Hao Tang, Chengji Dong, Bo Wang, Mengran Liu, Zhaoyue Li, Yingfeng Tu
{"title":"Multi-omic underpinnings of heterogeneous aging across multiple organ systems.","authors":"Jie Xiong, Xiaoting Zhu, Yutong Guo, Hao Tang, Chengji Dong, Bo Wang, Mengran Liu, Zhaoyue Li, Yingfeng Tu","doi":"10.1016/j.xgen.2025.101032","DOIUrl":"https://doi.org/10.1016/j.xgen.2025.101032","url":null,"abstract":"<p><p>Aging is the main determinant of chronic diseases and mortality, yet organ-specific aging trajectories vary, and the molecular basis underlying this heterogeneity remains unclear. To elucidate this, we integrated genomic, epigenomic, transcriptomic, proteomic, and metabolomic data, employing post-genome-wide association study methodologies to systematically investigate the molecular mechanisms of nine organ-specific aging clocks and four blood-based epigenetic clocks. We uncovered genetic correlations and specific phenotypic clusters among these aging-related traits, identified prioritized genetic drug targets for heterogeneous aging, and elucidated downstream proteomic and metabolomic effects mediated by heterogeneous aging. We constructed a cross-layer molecular interaction network of heterogeneous aging across multiple organ systems and characterized detectable biomarkers of this heterogeneity. Integrating these findings, we developed an R/Shiny-based framework that provides a comprehensive multi-omic molecular landscape of heterogeneous aging, thereby advancing the understanding of aging heterogeneity and informing precision medicine strategies to delay organ-specific aging and prevent or treat its associated chronic diseases.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":" ","pages":"101032"},"PeriodicalIF":11.1,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145226413","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 : 2025-09-25DOI: 10.1016/j.xgen.2025.101012
Biaobang Chen, Weijie Wang, Juanzi Shi, Xiaoxi Sun, Yichun Guan, Guimin Hao, Junli Zhao, Jian Mu, Zhihua Zhang, Fangzhou Xu, Dengying Gao, Zhiqi Pan, Ran Yu, Hao Gu, Huizhen Fan, Yuxi Luo, Siyuan Xie, Xingzhu Du, Huixia Jing, Zhiqi Ye, Xuelin Zhang, Ruiqi Hai, Hongying Zhu, Tianyu Wu, Qiaoli Li, Jing Fu, Ling Wu, Wenjing Wang, Chunyi Li, Feiyang Diao, Qiuwen Shi, Lin Li, Shiru Xu, Da Li, Xi Dong, Peng Xu, Jiucun Wang, Lin He, Yanping Kuang, Qing Sang, Lei Wang
{"title":"Genetic landscape of human oocyte/embryo defects.","authors":"Biaobang Chen, Weijie Wang, Juanzi Shi, Xiaoxi Sun, Yichun Guan, Guimin Hao, Junli Zhao, Jian Mu, Zhihua Zhang, Fangzhou Xu, Dengying Gao, Zhiqi Pan, Ran Yu, Hao Gu, Huizhen Fan, Yuxi Luo, Siyuan Xie, Xingzhu Du, Huixia Jing, Zhiqi Ye, Xuelin Zhang, Ruiqi Hai, Hongying Zhu, Tianyu Wu, Qiaoli Li, Jing Fu, Ling Wu, Wenjing Wang, Chunyi Li, Feiyang Diao, Qiuwen Shi, Lin Li, Shiru Xu, Da Li, Xi Dong, Peng Xu, Jiucun Wang, Lin He, Yanping Kuang, Qing Sang, Lei Wang","doi":"10.1016/j.xgen.2025.101012","DOIUrl":"https://doi.org/10.1016/j.xgen.2025.101012","url":null,"abstract":"<p><p>Oocyte/embryo defects can result in oocyte maturation arrest, fertilization failure, embryonic arrest, and infertility as well as recurrent in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) failures. However, the genetic determinants of human oocyte/embryo defects remain largely unknown, and the overall genetic diagnostic yield for such defects has not been evaluated. Here, we performed exome sequencing in 3,627 patients with oocyte/embryo defects. We identified a total of 479 positive cases carrying variants in 37 known genes, indicating a diagnostic yield of 13.2%. Case-control association studies combined with gene set enrichment analysis identified 123 novel candidate genes responsible for oocyte/embryo defects. These results provide a comprehensive genetic landscape of human oocyte/embryo defects and highlight the clinical significance of genetic counseling in infertile patients with oocyte/embryo defects. Our study will lay the foundation for transforming the traditional clinical practice for failed IVF/ICSI attempts into genetic-based precision and personalized treatment for these patients.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":" ","pages":"101012"},"PeriodicalIF":11.1,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145180657","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 : 2025-09-24DOI: 10.1016/j.xgen.2025.101010
Alice Franklin, Jonathan P Davies, Nicholas E Clifton, Georgina E T Blake, Rosemary Bamford, Emma M Walker, Barry Chioza, Martyn Frith, Joe Burrage, Nick Owens, Shyam Prabhakar, Emma Dempster, Eilis Hannon, Jonathan Mill
{"title":"Cell-type-specific DNA methylation dynamics in the prenatal and postnatal human cortex.","authors":"Alice Franklin, Jonathan P Davies, Nicholas E Clifton, Georgina E T Blake, Rosemary Bamford, Emma M Walker, Barry Chioza, Martyn Frith, Joe Burrage, Nick Owens, Shyam Prabhakar, Emma Dempster, Eilis Hannon, Jonathan Mill","doi":"10.1016/j.xgen.2025.101010","DOIUrl":"https://doi.org/10.1016/j.xgen.2025.101010","url":null,"abstract":"<p><p>The human cortex undergoes extensive epigenetic remodeling during development, although the precise temporal and cell-type-specific dynamics of DNA methylation remain incompletely understood. In this study, we profiled genome-wide DNA methylation across human cortex tissue from donors aged 6 post-conception weeks to 108 years of age. We observed widespread, developmentally regulated changes in DNA methylation, with pronounced shifts occurring during early- and mid-gestation that were distinct from age-associated modifications in the postnatal cortex. Using fluorescence-activated nuclei sorting, we optimized a protocol for the isolation of SATB2-positive neuronal nuclei, enabling the identification of cell-type-specific DNA methylation trajectories in the developing cortex. Developmentally dynamic DNA methylation sites were significantly enriched near genes implicated in autism and schizophrenia, supporting a role for epigenetic dysregulation in neurodevelopmental conditions. Our findings underscore the prenatal period as a critical window of epigenomic plasticity in the brain with important implications for understanding the genetic basis of neurodevelopmental phenotypes.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":" ","pages":"101010"},"PeriodicalIF":11.1,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145151986","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 : 2025-09-24DOI: 10.1016/j.xgen.2025.101011
Petr Šulc, Andrea Di Gioacchino, Alexander Solovyov, Siyu Sun, Stephen Martis, Sajid A Marhon, Håvard T Lindholm, Raymond Chen, Amir Hosseini, Hua Jiang, Bao-Han Ly, Martin S Taylor, Parinaz Mehdipour, Omar Abdel-Wahab, Nicole Rusk, Nicolas Vabret, John LaCava, Daniel D De Carvalho, Rémi Monasson, Simona Cocco, Benjamin D Greenbaum
{"title":"Repeats mimic pathogen-associated patterns across a vast evolutionary landscape.","authors":"Petr Šulc, Andrea Di Gioacchino, Alexander Solovyov, Siyu Sun, Stephen Martis, Sajid A Marhon, Håvard T Lindholm, Raymond Chen, Amir Hosseini, Hua Jiang, Bao-Han Ly, Martin S Taylor, Parinaz Mehdipour, Omar Abdel-Wahab, Nicole Rusk, Nicolas Vabret, John LaCava, Daniel D De Carvalho, Rémi Monasson, Simona Cocco, Benjamin D Greenbaum","doi":"10.1016/j.xgen.2025.101011","DOIUrl":"https://doi.org/10.1016/j.xgen.2025.101011","url":null,"abstract":"<p><p>An emerging hallmark of many human diseases is transcription of typically silenced repetitive DNA containing pathogen-associated molecular patterns (PAMPs). These PAMPs engage the innate immune system via pattern recognition receptors (PRRs)-a phenomenon known as viral mimicry. We propose a statistical physics framework to quantify viral mimicry by measuring \"selective forces\" that enrich PAMPs compared to a genome-wide reference distribution. We validate our predictions by identifying repeats that bind different PRRs and show potential viral mimics in different repeat families across eukaryotic genomes, suggesting shared mechanisms drive emergence and retention. We propose two non-exclusive evolutionary hypotheses. The first \"repeat-centric\" hypothesis posits PAMPs are integral to the repeat life cycle and are therefore enriched as they mediate repeat expansion. The second \"organism-centric\" hypothesis proposes viral mimicry functions as a cell-intrinsic feedback mechanism for sensing and reacting to transcriptional dysregulation, which provides a selective pressure to maintain PAMPs in genomes.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":" ","pages":"101011"},"PeriodicalIF":11.1,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145151953","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 : 2025-09-24DOI: 10.1016/j.xgen.2025.101005
Marisa Loach, Amirhossein Naghsh Nilchi, Diana Chiang, Morgan Howells, Florian Heyl, Helena Rasche, Julia Jakiela, Mehmet Tekman, Menna Gamal, Pablo Moreno, Saskia Hiltemann, Timon Schlegel, Björn Grüning, Rolf Backofen, Pavankumar Videm, Wendi Bacon
{"title":"Galaxy single-cell & spatial omics community update: Navigating new frontiers in 2025.","authors":"Marisa Loach, Amirhossein Naghsh Nilchi, Diana Chiang, Morgan Howells, Florian Heyl, Helena Rasche, Julia Jakiela, Mehmet Tekman, Menna Gamal, Pablo Moreno, Saskia Hiltemann, Timon Schlegel, Björn Grüning, Rolf Backofen, Pavankumar Videm, Wendi Bacon","doi":"10.1016/j.xgen.2025.101005","DOIUrl":"https://doi.org/10.1016/j.xgen.2025.101005","url":null,"abstract":"<p><p>Single-cell omics, named Method of the Year three times, have revolutionized biological research by enabling the high-resolution exploration of cellular heterogeneity and molecular processes. Initially centered on transcriptomics, this rapidly evolving field now ranges from multiomics to spatial analysis, with expanding customization options. The ubiquity of such analyses and the lack of a unified pipeline necessitate the development of scalable, flexible, and integrated tools and workflows. The Galaxy platform has responded to these technological advancements, extending its repertoire of freely accessible tools and workflows, backed by expert-reviewed and user-informed training resources to empower researchers to perform and interpret their own analyses. With more than 175 tools, 120 training resources, and 300,000 jobs running at the time of writing, this process has culminated in the development of Galaxy single-cell and spatial omics community (SPOC), designed to promote global collaboration in advancing usable, reproducible, accessible, and sustainable single-cell and spatial omics research.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":" ","pages":"101005"},"PeriodicalIF":11.1,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145152020","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 : 2025-09-18DOI: 10.1016/j.xgen.2025.101009
Xihao Li, Andrew R Wood, Yuxin Yuan, Manrui Zhang, Yushu Huang, Gareth Hawkes, Robin N Beaumont, Michael N Weedon, Wenyuan Li, Xiaoyu Li, Xihong Lin, Zilin Li
{"title":"Streamlining large-scale genomic data management: Insights from the UK Biobank whole-genome sequencing data.","authors":"Xihao Li, Andrew R Wood, Yuxin Yuan, Manrui Zhang, Yushu Huang, Gareth Hawkes, Robin N Beaumont, Michael N Weedon, Wenyuan Li, Xiaoyu Li, Xihong Lin, Zilin Li","doi":"10.1016/j.xgen.2025.101009","DOIUrl":"10.1016/j.xgen.2025.101009","url":null,"abstract":"<p><p>Biobank-scale whole-genome sequencing (WGS) studies are increasingly pivotal in unraveling the genetic bases of diverse health outcomes. However, managing and analyzing these datasets' sheer volume and complexity presents significant challenges. We highlight the annotated genomic data structure (aGDS) format, substantially reducing the WGS data file size while enabling seamless integration of genomic and functional information for comprehensive WGS analyses. The aGDS format yielded 23 chromosome-specific files for the UK Biobank 500k WGS dataset, occupying only 1.10 tebibytes of storage. We develop the vcf2agds toolkit that streamlines the conversion of WGS data from VCF to aGDS format. Additionally, the STAARpipeline equipped with the aGDS files enabled scalable, comprehensive, and functionally informed WGS analysis, facilitating the detection of common and rare coding and noncoding phenotype-genotype associations. Overall, the vcf2agds toolkit and STAARpipeline provide a streamlined solution that facilitates efficient data management and analysis of biobank-scale WGS data across hundreds of thousands of samples.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":" ","pages":"101009"},"PeriodicalIF":11.1,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145093020","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 : 2025-09-18DOI: 10.1016/j.xgen.2025.101003
Chirag Gupta, Noah Cohen Kalafut, Declan Clarke, Jerome J Choi, Kalpana Hanthanan Arachchilage, Saniya Khullar, Yan Xia, Xiao Zhou, Cagatay Dursun, Mark Gerstein, Daifeng Wang
{"title":"Network-based drug repurposing for psychiatric disorders using single-cell genomics.","authors":"Chirag Gupta, Noah Cohen Kalafut, Declan Clarke, Jerome J Choi, Kalpana Hanthanan Arachchilage, Saniya Khullar, Yan Xia, Xiao Zhou, Cagatay Dursun, Mark Gerstein, Daifeng Wang","doi":"10.1016/j.xgen.2025.101003","DOIUrl":"10.1016/j.xgen.2025.101003","url":null,"abstract":"<p><p>Neuropsychiatric disorders lack effective treatments due to a limited understanding of the underlying cellular and molecular mechanisms. To address this, we integrated population-scale single-cell genomics data and analyzed 23 cell-type-level gene regulatory networks across schizophrenia, bipolar disorder, and autism. Our analysis revealed potential druggable transcription factors co-regulating known risk genes that converge into cell-type-specific co-regulated modules. We applied graph neural networks on those modules to prioritize novel risk genes and leveraged them in a network-based drug repurposing framework to identify 220 drug molecules with the potential for targeting specific cell types. We found evidence for 37 of these drugs in reversing disorder-associated transcriptional phenotypes. Additionally, we discovered 335 drug-cell quantitative trait loci (eQTLs), revealing genetic variation's influence on drug target expression at the cell-type level. Our results provide a single-cell network medicine resource that provides potential mechanistic insights for advancing treatment options for neuropsychiatric disorders.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":" ","pages":"101003"},"PeriodicalIF":11.1,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145093034","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 : 2025-09-17DOI: 10.1016/j.xgen.2025.100986
Kristina M Yim, Marybeth Baumgartner, Martina Krenzer, María F Rosales Larios, Guillermina Hill-Terán, Timothy Nottoli, Rebecca A Muhle, James P Noonan
{"title":"Cell-type-specific dysregulation of gene expression due to Chd8 haploinsufficiency during mouse cortical development.","authors":"Kristina M Yim, Marybeth Baumgartner, Martina Krenzer, María F Rosales Larios, Guillermina Hill-Terán, Timothy Nottoli, Rebecca A Muhle, James P Noonan","doi":"10.1016/j.xgen.2025.100986","DOIUrl":"10.1016/j.xgen.2025.100986","url":null,"abstract":"<p><p>Disruptive variants in the chromodomain helicase CHD8 are associated with risk for autism spectrum disorder (ASD). CHD8 haploinsufficiency is hypothesized to contribute to ASD by perturbing neurodevelopmental gene expression. However, insight into cell-type-specific transcriptional effects of CHD8 haploinsufficiency remains limited. We used single-cell and single-nucleus RNA sequencing to identify dysregulated genes in the embryonic and juvenile Chd8<sup>+/-</sup> mouse cortex. Chd8 and other ASD risk-associated genes showed a convergent expression trajectory conserved between mouse and human developing cortex, increasing from progenitor zones to the cortical plate. Genes associated with neurodevelopmental disorders or involved in chromatin remodeling and neuron projection development were dysregulated in Chd8<sup>+/-</sup> embryonic radial glia. Genes implicated in synaptic activity and organization were dysregulated in Chd8<sup>+/-</sup> postnatal excitatory cortical neurons, suggesting impaired synaptogenesis. Our findings reveal complex patterns of transcriptional dysregulation due to Chd8 haploinsufficiency, potentially with distinct impacts on progenitors and maturing neurons in the excitatory neuronal lineage.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":" ","pages":"100986"},"PeriodicalIF":11.1,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145088403","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 : 2025-09-17DOI: 10.1016/j.xgen.2025.101007
Paul M McKeever, Aiden M Sababi, Raghav Sharma, Zhiyu Xu, Shangxi Xiao, Philip McGoldrick, Troy Ketela, Christine Sato, Danielle Moreno, Naomi Visanji, Gabor G Kovacs, Julia Keith, Lorne Zinman, Ekaterina Rogaeva, Hani Goodarzi, Gary D Bader, Janice Robertson
{"title":"Single-nucleus transcriptome atlas of orbitofrontal cortex in ALS with a deep learning-based decoding of alternative polyadenylation mechanisms.","authors":"Paul M McKeever, Aiden M Sababi, Raghav Sharma, Zhiyu Xu, Shangxi Xiao, Philip McGoldrick, Troy Ketela, Christine Sato, Danielle Moreno, Naomi Visanji, Gabor G Kovacs, Julia Keith, Lorne Zinman, Ekaterina Rogaeva, Hani Goodarzi, Gary D Bader, Janice Robertson","doi":"10.1016/j.xgen.2025.101007","DOIUrl":"10.1016/j.xgen.2025.101007","url":null,"abstract":"<p><p>Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are fatal neurodegenerative diseases sharing clinical and pathological features. Both involve complex neuron-glia interactions, but cell-type-specific alterations remain poorly defined. We performed single-nucleus RNA sequencing of the frontal cortex from C9orf72-related ALS (with and without FTLD) and sporadic ALS (sALS). Neurons showed prominent changes in mitochondrial function, protein homeostasis, and chromatin remodeling. Comparison with independent datasets from other cortical regions revealed consistent pathway alterations, including upregulation of STMN2 and NEFL across brain regions and subtypes. We further examined dysregulation of alternative polyadenylation (APA), an understudied post-transcriptional mechanism, uncovering cell-type-specific APA patterns. To investigate its regulation, we developed the alternative polyadenylation network (APA-Net), a multi-modal deep learning model integrating transcript sequences and RNA-binding protein (RBP) expression profiles to predict APA. This atlas advances our understanding of ALS/FTLD molecular pathology and provides a valuable resource for future mechanistic studies.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":" ","pages":"101007"},"PeriodicalIF":11.1,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145088500","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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