Cell genomicsPub Date : 2024-08-26DOI: 10.1016/j.xgen.2024.100642
Hüseyin Tayran, Elanur Yilmaz, Prabesh Bhattarai, Yuhao Min, Xue Wang, Yiyi Ma, Ni Wang, Inyoung Jeong, Nastasia Nelson, Nada Kassara, Mehmet Ilyas Cosacak, Ruya Merve Dogru, Dolly Reyes-Dumeyer, Jakob Mørkved Stenersen, Joseph S Reddy, Min Qiao, Delaney Flaherty, Tamil Iniyan Gunasekaran, Zikun Yang, Nathalie Jurisch-Yaksi, Andrew F Teich, Takahisa Kanekiyo, Giuseppe Tosto, Badri N Vardarajan, Özkan İş, Nilüfer Ertekin-Taner, Richard Mayeux, Caghan Kizil
{"title":"ABCA7-dependent induction of neuropeptide Y is required for synaptic resilience in Alzheimer's disease through BDNF/NGFR signaling.","authors":"Hüseyin Tayran, Elanur Yilmaz, Prabesh Bhattarai, Yuhao Min, Xue Wang, Yiyi Ma, Ni Wang, Inyoung Jeong, Nastasia Nelson, Nada Kassara, Mehmet Ilyas Cosacak, Ruya Merve Dogru, Dolly Reyes-Dumeyer, Jakob Mørkved Stenersen, Joseph S Reddy, Min Qiao, Delaney Flaherty, Tamil Iniyan Gunasekaran, Zikun Yang, Nathalie Jurisch-Yaksi, Andrew F Teich, Takahisa Kanekiyo, Giuseppe Tosto, Badri N Vardarajan, Özkan İş, Nilüfer Ertekin-Taner, Richard Mayeux, Caghan Kizil","doi":"10.1016/j.xgen.2024.100642","DOIUrl":"https://doi.org/10.1016/j.xgen.2024.100642","url":null,"abstract":"<p><p>Genetic variants in ABCA7, an Alzheimer's disease (AD)-associated gene, elevate AD risk, yet its functional relevance to the etiology is unclear. We generated a CRISPR-Cas9-mediated abca7 knockout zebrafish to explore ABCA7's role in AD. Single-cell transcriptomics in heterozygous abca7<sup>+/-</sup> knockout combined with Aβ42 toxicity revealed that ABCA7 is crucial for neuropeptide Y (NPY), brain-derived neurotrophic factor (BDNF), and nerve growth factor receptor (NGFR) expressions, which are crucial for synaptic integrity, astroglial proliferation, and microglial prevalence. Impaired NPY induction decreased BDNF and synaptic density, which are rescuable with ectopic NPY. In induced pluripotent stem cell-derived human neurons exposed to Aβ42, ABCA7<sup>-/-</sup> suppresses NPY. Clinical data showed reduced NPY in AD correlated with elevated Braak stages, genetic variants in NPY associated with AD, and epigenetic changes in NPY, NGFR, and BDNF promoters linked to ABCA7 variants. Therefore, ABCA7-dependent NPY signaling via BDNF-NGFR maintains synaptic integrity, implicating its impairment in increased AD risk through reduced brain resilience.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":null,"pages":null},"PeriodicalIF":11.1,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142115575","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 : 2024-08-23DOI: 10.1016/j.xgen.2024.100641
Zhongxiao Li, Bin Zhang, Jia Jia Chan, Hossein Tabatabaeian, Qing Yun Tong, Xiao Hong Chew, Xiaonan Fan, Patrick Driguez, Charlene Chan, Faith Cheong, Shi Wang, Bei En Siew, Ian Jse-Wei Tan, Kai-Yin Lee, Bettina Lieske, Wai-Kit Cheong, Dennis Kappei, Ker-Kan Tan, Xin Gao, Yvonne Tay
{"title":"An isoform-resolution transcriptomic atlas of colorectal cancer from long-read single-cell sequencing.","authors":"Zhongxiao Li, Bin Zhang, Jia Jia Chan, Hossein Tabatabaeian, Qing Yun Tong, Xiao Hong Chew, Xiaonan Fan, Patrick Driguez, Charlene Chan, Faith Cheong, Shi Wang, Bei En Siew, Ian Jse-Wei Tan, Kai-Yin Lee, Bettina Lieske, Wai-Kit Cheong, Dennis Kappei, Ker-Kan Tan, Xin Gao, Yvonne Tay","doi":"10.1016/j.xgen.2024.100641","DOIUrl":"https://doi.org/10.1016/j.xgen.2024.100641","url":null,"abstract":"<p><p>Colorectal cancer (CRC) ranks as the second leading cause of cancer deaths globally. In recent years, short-read single-cell RNA sequencing (scRNA-seq) has been instrumental in deciphering tumor heterogeneities. However, these studies only enable gene-level quantification but neglect alterations in transcript structures arising from alternative end processing or splicing. In this study, we integrated short- and long-read scRNA-seq of CRC samples to build an isoform-resolution CRC transcriptomic atlas. We identified 394 dysregulated transcript structures in tumor epithelial cells, including 299 resulting from various combinations of splicing events. Second, we characterized genes and isoforms associated with epithelial lineages and subpopulations exhibiting distinct prognoses. Among 31,935 isoforms with novel junctions, 330 were supported by The Cancer Genome Atlas RNA-seq and mass spectrometry data. Finally, we built an algorithm that integrated novel peptides derived from open reading frames of recurrent tumor-specific transcripts with mass spectrometry data and identified recurring neoepitopes that may aid the development of cancer vaccines.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":null,"pages":null},"PeriodicalIF":11.1,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142115576","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 : 2024-08-23DOI: 10.1016/j.xgen.2024.100637
Leah L Weber, Derek Reiman, Mrinmoy S Roddur, Yuanyuan Qi, Mohammed El-Kebir, Aly A Khan
{"title":"Isotype-aware inference of B cell clonal lineage trees from single-cell sequencing data.","authors":"Leah L Weber, Derek Reiman, Mrinmoy S Roddur, Yuanyuan Qi, Mohammed El-Kebir, Aly A Khan","doi":"10.1016/j.xgen.2024.100637","DOIUrl":"10.1016/j.xgen.2024.100637","url":null,"abstract":"<p><p>Single-cell RNA sequencing (scRNA-seq) enables comprehensive characterization of the micro-evolutionary processes of B cells during an adaptive immune response, capturing features of somatic hypermutation (SHM) and class switch recombination (CSR). Existing phylogenetic approaches for reconstructing B cell evolution have primarily focused on the SHM process alone. Here, we present tree inference of B cell clonal lineages (TRIBAL), an algorithm designed to optimally reconstruct the evolutionary history of B cell clonal lineages undergoing both SHM and CSR from scRNA-seq data. Through simulations, we demonstrate that TRIBAL produces more comprehensive and accurate B cell lineage trees compared to existing methods. Using real-world datasets, TRIBAL successfully recapitulates expected biological trends in a model affinity maturation system while reconstructing evolutionary histories with more parsimonious class switching than state-of-the-art methods. Thus, TRIBAL significantly improves B cell lineage tracing, useful for modeling vaccine responses, disease progression, and the identification of therapeutic antibodies.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":null,"pages":null},"PeriodicalIF":11.1,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142115577","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 : 2024-08-21DOI: 10.1016/j.xgen.2024.100639
Rodrigo Martín, Nicolás Gaitán, Frédéric Jarlier, Lars Feuerbach, Henri de Soyres, Marc Arbonés, Tom Gutman, Montserrat Puiggròs, Alvaro Ferriz, Asier Gonzalez, Lucía Estelles, Ivo Gut, Salvador Capella-Gutierrez, Lincoln D Stein, Benedikt Brors, Romina Royo, Philippe Hupé, David Torrents
{"title":"ONCOLINER: A new solution for monitoring, improving, and harmonizing somatic variant calling across genomic oncology centers.","authors":"Rodrigo Martín, Nicolás Gaitán, Frédéric Jarlier, Lars Feuerbach, Henri de Soyres, Marc Arbonés, Tom Gutman, Montserrat Puiggròs, Alvaro Ferriz, Asier Gonzalez, Lucía Estelles, Ivo Gut, Salvador Capella-Gutierrez, Lincoln D Stein, Benedikt Brors, Romina Royo, Philippe Hupé, David Torrents","doi":"10.1016/j.xgen.2024.100639","DOIUrl":"https://doi.org/10.1016/j.xgen.2024.100639","url":null,"abstract":"<p><p>The characterization of somatic genomic variation associated with the biology of tumors is fundamental for cancer research and personalized medicine, as it guides the reliability and impact of cancer studies and genomic-based decisions in clinical oncology. However, the quality and scope of tumor genome analysis across cancer research centers and hospitals are currently highly heterogeneous, limiting the consistency of tumor diagnoses across hospitals and the possibilities of data sharing and data integration across studies. With the aim of providing users with actionable and personalized recommendations for the overall enhancement and harmonization of somatic variant identification across research and clinical environments, we have developed ONCOLINER. Using specifically designed mosaic and tumorized genomes for the analysis of recall and precision across somatic SNVs, insertions or deletions (indels), and structural variants (SVs), we demonstrate that ONCOLINER is capable of improving and harmonizing genome analysis across three state-of-the-art variant discovery pipelines in genomic oncology.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":null,"pages":null},"PeriodicalIF":11.1,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142115578","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 : 2024-08-21DOI: 10.1016/j.xgen.2024.100636
Sarah Djeddi, Daniela Fernandez-Salinas, George X Huang, Vitor R C Aguiar, Chitrasen Mohanty, Christina Kendziorski, Steven Gazal, Joshua A Boyce, Carole Ober, James E Gern, Nora A Barrett, Maria Gutierrez-Arcelus
{"title":"Rhinovirus infection of airway epithelial cells uncovers the non-ciliated subset as a likely driver of genetic risk to childhood-onset asthma.","authors":"Sarah Djeddi, Daniela Fernandez-Salinas, George X Huang, Vitor R C Aguiar, Chitrasen Mohanty, Christina Kendziorski, Steven Gazal, Joshua A Boyce, Carole Ober, James E Gern, Nora A Barrett, Maria Gutierrez-Arcelus","doi":"10.1016/j.xgen.2024.100636","DOIUrl":"10.1016/j.xgen.2024.100636","url":null,"abstract":"<p><p>Asthma is a complex disease caused by genetic and environmental factors. Studies show that wheezing during rhinovirus infection correlates with childhood asthma development. Over 150 non-coding risk variants for asthma have been identified, many affecting gene regulation in T cells, but the effects of most risk variants remain unknown. We hypothesized that airway epithelial cells could also mediate genetic susceptibility to asthma given they are the first line of defense against respiratory viruses and allergens. We integrated genetic data with transcriptomics of airway epithelial cells subject to different stimuli. We demonstrate that rhinovirus infection significantly upregulates childhood-onset asthma-associated genes, particularly in non-ciliated cells. This enrichment is also observed with influenza infection but not with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or cytokine activation. Overall, our results suggest that rhinovirus infection is an environmental factor that interacts with genetic risk factors through non-ciliated airway epithelial cells to drive childhood-onset asthma.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":null,"pages":null},"PeriodicalIF":11.1,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142094262","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 : 2024-08-14DOI: 10.1016/j.xgen.2024.100635
Dana Tseitline, Yuval Cohen, Sheera Adar
{"title":"Genomic patterns of somatic mutations provide new prognostic, therapeutic, and biological insights in cancer.","authors":"Dana Tseitline, Yuval Cohen, Sheera Adar","doi":"10.1016/j.xgen.2024.100635","DOIUrl":"https://doi.org/10.1016/j.xgen.2024.100635","url":null,"abstract":"<p><p>The mutational landscape of an individual's cancer can inform on its molecular state and be used as prognostic and therapeutic markers. The study by Barbour et al.<sup>1</sup> analyzes mutational patterns in bladder cancer samples to uncover new biological insights into the ERCC2 gene function and develop new predictive prognostic tools.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":null,"pages":null},"PeriodicalIF":11.1,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141989626","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 : 2024-08-14Epub Date: 2024-07-10DOI: 10.1016/j.xgen.2024.100606
Katelyn R Titus, Zoltan Simandi, Harshini Chandrashekar, Dominik Paquet, Jennifer E Phillips-Cremins
{"title":"Cell-type-specific loops linked to RNA polymerase II elongation in human neural differentiation.","authors":"Katelyn R Titus, Zoltan Simandi, Harshini Chandrashekar, Dominik Paquet, Jennifer E Phillips-Cremins","doi":"10.1016/j.xgen.2024.100606","DOIUrl":"10.1016/j.xgen.2024.100606","url":null,"abstract":"<p><p>DNA is folded into higher-order structures that shape and are shaped by genome function. The role of long-range loops in the establishment of new gene expression patterns during cell fate transitions remains poorly understood. Here, we investigate the link between cell-specific loops and RNA polymerase II (RNA Pol II) during neural lineage commitment. We find thousands of loops decommissioned or gained de novo upon differentiation of human induced pluripotent stem cells (hiPSCs) to neural progenitor cells (NPCs) and post-mitotic neurons. During hiPSC-to-NPC and NPC-to-neuron transitions, genes changing from RNA Pol II initiation to elongation are >4-fold more likely to anchor cell-specific loops than repressed genes. Elongated genes exhibit significant mRNA upregulation when connected in cell-specific promoter-enhancer loops but not invariant promoter-enhancer loops or promoter-promoter loops or when unlooped. Genes transitioning from repression to RNA Pol II initiation exhibit a slight mRNA increase independent of loop status. Our data link cell-specific loops and robust RNA Pol II-mediated elongation during neural cell fate transitions.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":null,"pages":null},"PeriodicalIF":11.1,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141592262","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}
{"title":"Crosstalk between epitranscriptomic and epigenomic modifications and its implication in human diseases.","authors":"Chengyu Li, Kexuan Chen, Qianchen Fang, Shaohui Shi, Jiuhong Nan, Jialin He, Yafei Yin, Xiaoyu Li, Jingyun Li, Lei Hou, Xinyang Hu, Manolis Kellis, Xikun Han, Xushen Xiong","doi":"10.1016/j.xgen.2024.100605","DOIUrl":"10.1016/j.xgen.2024.100605","url":null,"abstract":"<p><p>Crosstalk between N<sup>6</sup>-methyladenosine (m<sup>6</sup>A) and epigenomes is crucial for gene regulation, but its regulatory directionality and disease significance remain unclear. Here, we utilize quantitative trait loci (QTLs) as genetic instruments to delineate directional maps of crosstalk between m<sup>6</sup>A and two epigenomic traits, DNA methylation (DNAme) and H3K27ac. We identify 47 m<sup>6</sup>A-to-H3K27ac and 4,733 m<sup>6</sup>A-to-DNAme and, in the reverse direction, 106 H3K27ac-to-m<sup>6</sup>A and 61,775 DNAme-to-m<sup>6</sup>A regulatory loci, with differential genomic location preference observed for different regulatory directions. Integrating these maps with complex diseases, we prioritize 20 genome-wide association study (GWAS) loci for neuroticism, depression, and narcolepsy in brain; 1,767 variants for asthma and expiratory flow traits in lung; and 249 for coronary artery disease, blood pressure, and pulse rate in muscle. This study establishes disease regulatory paths, such as rs3768410-DNAme-m<sup>6</sup>A-asthma and rs56104944-m<sup>6</sup>A-DNAme-hypertension, uncovering locus-specific crosstalk between m<sup>6</sup>A and epigenomic layers and offering insights into regulatory circuits underlying human diseases.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":null,"pages":null},"PeriodicalIF":11.1,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141565286","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 : 2024-08-14Epub Date: 2024-07-30DOI: 10.1016/j.xgen.2024.100626
Shenghan Gao, Yanyan Jia, Hongtao Guo, Tun Xu, Bo Wang, Stephen J Bush, Shijie Wan, Yimeng Zhang, Xiaofei Yang, Kai Ye
{"title":"The centromere landscapes of four karyotypically diverse Papaver species provide insights into chromosome evolution and speciation.","authors":"Shenghan Gao, Yanyan Jia, Hongtao Guo, Tun Xu, Bo Wang, Stephen J Bush, Shijie Wan, Yimeng Zhang, Xiaofei Yang, Kai Ye","doi":"10.1016/j.xgen.2024.100626","DOIUrl":"10.1016/j.xgen.2024.100626","url":null,"abstract":"<p><p>Understanding the roles played by centromeres in chromosome evolution and speciation is complicated by the fact that centromeres comprise large arrays of tandemly repeated satellite DNA, which hinders high-quality assembly. Here, we used long-read sequencing to generate nearly complete genome assemblies for four karyotypically diverse Papaver species, P. setigerum (2n = 44), P. somniferum (2n = 22), P. rhoeas (2n = 14), and P. bracteatum (2n = 14), collectively representing 45 gapless centromeres. We identified four centromere satellite (cenSat) families and experimentally validated two representatives. For the two allopolyploid genomes (P. somniferum and P. setigerum), we characterized the subgenomic distribution of each satellite and identified a \"homogenizing\" phase of centromere evolution in the aftermath of hybridization. An interspecies comparison of the peri-centromeric regions further revealed extensive centromere-mediated chromosome rearrangements. Taking these results together, we propose a model for studying cenSat competition after hybridization and shed further light on the complex role of the centromere in speciation.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":null,"pages":null},"PeriodicalIF":11.1,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141861840","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}