Pub 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
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+/- 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-/- 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.
{"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}
Pub 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
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.
{"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}
Pub 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
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.
单细胞 RNA 测序(scRNA-seq)能全面描述适应性免疫反应过程中 B 细胞的微进化过程,捕捉体细胞超突变(SHM)和类开关重组(CSR)的特征。现有的重建 B 细胞进化的系统发生学方法主要只关注 SHM 过程。在这里,我们介绍了B细胞克隆系的树推断(TRIBAL),这是一种旨在从scRNA-seq数据中优化重建同时经历SHM和CSR的B细胞克隆系进化史的算法。通过模拟,我们证明与现有方法相比,TRIBAL 能生成更全面、更准确的 B 细胞系树。利用真实世界的数据集,TRIBAL 成功地再现了模型亲和力成熟系统中预期的生物学趋势,同时与最先进的方法相比,TRIBAL 以更简洁的类别切换重建了进化史。因此,TRIBAL 显著改善了 B 细胞系的追踪,对疫苗反应建模、疾病进展和治疗性抗体的鉴定非常有用。
{"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}
Pub 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
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.
{"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}
Pub 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
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.
哮喘是一种由遗传和环境因素引起的复杂疾病。研究表明,鼻病毒感染时的喘息与儿童哮喘的发生有关。目前已发现 150 多种哮喘的非编码风险变异,其中许多影响 T 细胞的基因调控,但大多数风险变异的影响仍然未知。鉴于气道上皮细胞是抵御呼吸道病毒和过敏原的第一道防线,我们假设气道上皮细胞也可能介导哮喘的遗传易感性。我们将遗传数据与受到不同刺激的气道上皮细胞的转录组学进行了整合。我们证明,鼻病毒感染会显著上调儿童期发病的哮喘相关基因,尤其是在非纤毛细胞中。在感染流感时也能观察到这种富集现象,但在感染严重急性呼吸系统综合征冠状病毒 2(SARS-CoV-2)或细胞因子激活时却观察不到。总之,我们的研究结果表明,鼻病毒感染是一种环境因素,它通过非纤毛气道上皮细胞与遗传风险因素相互作用,导致儿童发病型哮喘。
{"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}
Pub Date : 2024-08-14DOI: 10.1016/j.xgen.2024.100635
Dana Tseitline, Yuval Cohen, Sheera Adar
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.1 analyzes mutational patterns in bladder cancer samples to uncover new biological insights into the ERCC2 gene function and develop new predictive prognostic tools.
{"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}
Pub 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
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.
DNA 折叠成高阶结构,形成基因组功能,并由基因组功能所形成。在细胞命运转换过程中,长程环路在建立新基因表达模式中的作用仍鲜为人知。在此,我们研究了在神经谱系承诺过程中细胞特异性环路与 RNA 聚合酶 II(RNA Pol II)之间的联系。我们发现,在人类诱导多能干细胞(hiPSC)分化为神经祖细胞(NPC)和有丝分裂后神经元的过程中,有数千个环路退役或新生。在hiPSC向NPC和NPC向神经元转变的过程中,从RNA Pol II起始转为伸长的基因锚定细胞特异性环路的可能性是被抑制基因的4倍以上。当伸长基因连接在细胞特异性启动子-增强子环路中,而不是不变的启动子-增强子环路或启动子-启动子环路中,或未连接时,会表现出显著的 mRNA 上调。从抑制状态过渡到 RNA Pol II 启动状态的基因表现出轻微的 mRNA 增加,与环路状态无关。我们的数据将神经细胞命运转变过程中细胞特异性环路和 RNA Pol II 介导的强健伸长联系起来。
{"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}
Crosstalk between N6-methyladenosine (m6A) 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 m6A and two epigenomic traits, DNA methylation (DNAme) and H3K27ac. We identify 47 m6A-to-H3K27ac and 4,733 m6A-to-DNAme and, in the reverse direction, 106 H3K27ac-to-m6A and 61,775 DNAme-to-m6A 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-m6A-asthma and rs56104944-m6A-DNAme-hypertension, uncovering locus-specific crosstalk between m6A and epigenomic layers and offering insights into regulatory circuits underlying human diseases.
{"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}
Pub 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
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.
由于中心粒由大量串联重复的卫星 DNA 阵列组成,阻碍了高质量的组装,因此了解中心粒在染色体进化和物种分化中的作用变得更加复杂。在这里,我们利用长线程测序技术为四个核型不同的巴布亚草物种(P. setigerum (2n = 44)、P. somniferum (2n = 22)、P. rhoeas (2n = 14) 和 P. bracteatum (2n = 14))生成了近乎完整的基因组组装,总共代表了 45 个无间隙中心粒。我们发现了四个中心粒卫星(cenSat)家族,并通过实验验证了其中两个代表。对于两个全多倍体基因组(P. somniferum 和 P. setigerum),我们描述了每个卫星的亚基因组分布,并确定了杂交后中心粒进化的 "同质化 "阶段。中心粒周围区域的种间比较进一步揭示了广泛的由中心粒介导的染色体重排。综合这些结果,我们提出了一个研究杂交后中心粒竞争的模型,并进一步揭示了中心粒在物种演化中的复杂作用。
{"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}