Pub Date : 2025-11-24DOI: 10.1038/s41588-025-02407-8
Ziyu Li, Gang Luo, Changpei Gan, Huayu Zhang, Ling Li, Xiaoxun Zhang, Xudong Xing, Simeng Hu, Xu Tan, Jingjing Ding, Liangjun Zhang, Ying Peng, Ziqian Xu, Qiong Pan, Christopher D. Byrne, Giovanni Targher, Xiao-Zhi Jin, Wei Xie, Xinshou Ouyang, Ming-Hua Zheng, Fan Bai, Jin Chai
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of chronic liver disease worldwide. We generated single-cell and spatial transcriptomic and metabolomic maps from 61 human livers, including controls (n = 10), metabolic dysfunction-associated steatotic liver (MASL) (n = 17) and metabolic dysfunction-associated steatohepatitis (MASH) (n = 34). We identified microphthalmia-associated transcription factor (MITF) as a key regulator of the lipid-handling capacity of lipid-associated macrophages (LAMs), and further revealed a hepato-protective role of LAMs mediated through hepatocyte growth factor secretion. Unbiased deconvolution of spatial transcriptomics delineated a fibrosis-associated gene program enriched in advanced MASH, suggesting profibrotic crosstalk between central vein endothelial and hepatic stellate cells within fibrotic regions. Mass spectrometry imaging-based spatial metabolomics demonstrated MASLD-specific accumulation of phospholipids, potentially linked to lipoprotein-associated phospholipase A2-mediated phospholipid metabolism in LAMs. This spatially resolved multi-omics atlas of human MASLD, which can be queried at the Human Masld Spatial Multiomics Atlas , provides a valuable resource for mechanistic and therapeutic studies. Spatially resolved transcriptomic, metabolomic and proteomic analyses of human liver samples highlight the role of lipid-associated macrophages in metabolic dysfunction-associated steatotic liver disease.
{"title":"Spatially resolved multi-omics of human metabolic dysfunction-associated steatotic liver disease","authors":"Ziyu Li, Gang Luo, Changpei Gan, Huayu Zhang, Ling Li, Xiaoxun Zhang, Xudong Xing, Simeng Hu, Xu Tan, Jingjing Ding, Liangjun Zhang, Ying Peng, Ziqian Xu, Qiong Pan, Christopher D. Byrne, Giovanni Targher, Xiao-Zhi Jin, Wei Xie, Xinshou Ouyang, Ming-Hua Zheng, Fan Bai, Jin Chai","doi":"10.1038/s41588-025-02407-8","DOIUrl":"10.1038/s41588-025-02407-8","url":null,"abstract":"Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of chronic liver disease worldwide. We generated single-cell and spatial transcriptomic and metabolomic maps from 61 human livers, including controls (n = 10), metabolic dysfunction-associated steatotic liver (MASL) (n = 17) and metabolic dysfunction-associated steatohepatitis (MASH) (n = 34). We identified microphthalmia-associated transcription factor (MITF) as a key regulator of the lipid-handling capacity of lipid-associated macrophages (LAMs), and further revealed a hepato-protective role of LAMs mediated through hepatocyte growth factor secretion. Unbiased deconvolution of spatial transcriptomics delineated a fibrosis-associated gene program enriched in advanced MASH, suggesting profibrotic crosstalk between central vein endothelial and hepatic stellate cells within fibrotic regions. Mass spectrometry imaging-based spatial metabolomics demonstrated MASLD-specific accumulation of phospholipids, potentially linked to lipoprotein-associated phospholipase A2-mediated phospholipid metabolism in LAMs. This spatially resolved multi-omics atlas of human MASLD, which can be queried at the Human Masld Spatial Multiomics Atlas , provides a valuable resource for mechanistic and therapeutic studies. Spatially resolved transcriptomic, metabolomic and proteomic analyses of human liver samples highlight the role of lipid-associated macrophages in metabolic dysfunction-associated steatotic liver disease.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 12","pages":"3112-3125"},"PeriodicalIF":29.0,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-025-02407-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145583019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-24DOI: 10.1038/s41588-025-02412-x
Sarah C. Nelson, Stephanie M. Gogarten, Jacklyn M. Dahlquist, Stephanie M. Fullerton
To inform deliberations around use of the Human Genome Diversity Project (HGDP) and related legacy data, we conducted a literature review of HGDP-derived data use from 2010 to 2024. Our analysis suggests broad re-use, possibly inconsistent with the original consent understandings. We urge caution with use of those data and similar datasets of unclear provenance.
{"title":"Human Genome Diversity Project data use and implications for the governance of legacy genomic data","authors":"Sarah C. Nelson, Stephanie M. Gogarten, Jacklyn M. Dahlquist, Stephanie M. Fullerton","doi":"10.1038/s41588-025-02412-x","DOIUrl":"10.1038/s41588-025-02412-x","url":null,"abstract":"To inform deliberations around use of the Human Genome Diversity Project (HGDP) and related legacy data, we conducted a literature review of HGDP-derived data use from 2010 to 2024. Our analysis suggests broad re-use, possibly inconsistent with the original consent understandings. We urge caution with use of those data and similar datasets of unclear provenance.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 12","pages":"2937-2941"},"PeriodicalIF":29.0,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145583023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-24DOI: 10.1038/s41588-025-02395-9
Johanna L. Smith, Clement A. Adebamowo, Sally N. Adebamowo, Burcu F. Darst, Stephanie M. Fullerton, Stephanie M. Gogarten, Marwan E. Hamed, Jibril B. Hirbo, Micah R. Hysong, Angad Singh Johar, Alyna T. Khan, Iftikhar J. Kullo, Iain R. Konigsberg, Peter Kraft, Leslie A. Lange, Yun Li, Alicia R. Martin, Sarah C. Nelson, Ananyo Choudhury, Michèle Ramsay, Ewan K. Cobran, Daniel J. Schaid, Jayati Sharma, Ying Wang, Genevieve L. Wojcik, Polygenic Risk Methods Development (PRIMED) Consortium, Quan Sun
The recent report from the National Academies of Sciences, Engineering and Medicine emphasizes the importance of detailed and tailored use of population descriptors in genomic analyses, but specific guidance for genomic data analysts is still lacking. In this Perspective, we focus on polygenic risk score (PRS) development and demonstrate that population descriptors are explicitly or implicitly involved in every step of the process. Attention to this matter is both an analytical concern and an ethical concern, as each decision has an impact on PRS results and performance across diverse populations. Drawing from the experience of the Polygenic Risk Methods Development (PRIMED) Consortium, we offer recommendations for applying population descriptors throughout the entire process of PRS development, validation and application. We urge the research community, particularly data analysts, to critically evaluate and justify their choices when using these descriptors to ensure both scientific rigor and research integrity. In this Perspective, authors from the Polygenic Risk Methods Development (PRIMED) Consortium highlight the ethical and analytical impact of population descriptors in polygenic risk score development and advocate for documenting detailed justifications.
{"title":"Recommendations for responsible use of population descriptors in polygenic risk score development","authors":"Johanna L. Smith, Clement A. Adebamowo, Sally N. Adebamowo, Burcu F. Darst, Stephanie M. Fullerton, Stephanie M. Gogarten, Marwan E. Hamed, Jibril B. Hirbo, Micah R. Hysong, Angad Singh Johar, Alyna T. Khan, Iftikhar J. Kullo, Iain R. Konigsberg, Peter Kraft, Leslie A. Lange, Yun Li, Alicia R. Martin, Sarah C. Nelson, Ananyo Choudhury, Michèle Ramsay, Ewan K. Cobran, Daniel J. Schaid, Jayati Sharma, Ying Wang, Genevieve L. Wojcik, Polygenic Risk Methods Development (PRIMED) Consortium, Quan Sun","doi":"10.1038/s41588-025-02395-9","DOIUrl":"10.1038/s41588-025-02395-9","url":null,"abstract":"The recent report from the National Academies of Sciences, Engineering and Medicine emphasizes the importance of detailed and tailored use of population descriptors in genomic analyses, but specific guidance for genomic data analysts is still lacking. In this Perspective, we focus on polygenic risk score (PRS) development and demonstrate that population descriptors are explicitly or implicitly involved in every step of the process. Attention to this matter is both an analytical concern and an ethical concern, as each decision has an impact on PRS results and performance across diverse populations. Drawing from the experience of the Polygenic Risk Methods Development (PRIMED) Consortium, we offer recommendations for applying population descriptors throughout the entire process of PRS development, validation and application. We urge the research community, particularly data analysts, to critically evaluate and justify their choices when using these descriptors to ensure both scientific rigor and research integrity. In this Perspective, authors from the Polygenic Risk Methods Development (PRIMED) Consortium highlight the ethical and analytical impact of population descriptors in polygenic risk score development and advocate for documenting detailed justifications.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 12","pages":"2962-2971"},"PeriodicalIF":29.0,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145596580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-24DOI: 10.1038/s41588-025-02400-1
Rose Orenbuch, Courtney A. Shearer, Aaron W. Kollasch, Aviv D. Spinner, Thomas Hopf, Lood van Niekerk, Dinko Franceschi, Mafalda Dias, Jonathan Frazer, Debora S. Marks
Missense variants remain a challenge in genetic interpretation owing to their subtle and context-dependent effects. Although current prediction models perform well in known disease genes, their scores are not calibrated across the proteome, limiting generalizability. To address this knowledge gap, we developed popEVE, a deep generative model combining evolutionary and human population data to estimate variant deleteriousness on a proteome-wide scale. popEVE achieves state-of-the-art performance without overestimating the burden of deleterious variants and identifies variants in 442 genes in a severe developmental disorder cohort, including 123 novel candidates. These genes are functionally similar to known disease genes, and their variants often localize to critical regions. Remarkably, popEVE can prioritize likely causal variants using only child exomes, enabling diagnosis even without parental sequencing. This work provides a generalizable framework for rare disease variant interpretation, especially in singleton cases, and demonstrates the utility of calibrated, evolution-informed scoring models for clinical genomics. popEVE is a proteome-wide deep generative model to identify and predict pathogenicity of missense mutations causing genetic disorders.
{"title":"Proteome-wide model for human disease genetics","authors":"Rose Orenbuch, Courtney A. Shearer, Aaron W. Kollasch, Aviv D. Spinner, Thomas Hopf, Lood van Niekerk, Dinko Franceschi, Mafalda Dias, Jonathan Frazer, Debora S. Marks","doi":"10.1038/s41588-025-02400-1","DOIUrl":"10.1038/s41588-025-02400-1","url":null,"abstract":"Missense variants remain a challenge in genetic interpretation owing to their subtle and context-dependent effects. Although current prediction models perform well in known disease genes, their scores are not calibrated across the proteome, limiting generalizability. To address this knowledge gap, we developed popEVE, a deep generative model combining evolutionary and human population data to estimate variant deleteriousness on a proteome-wide scale. popEVE achieves state-of-the-art performance without overestimating the burden of deleterious variants and identifies variants in 442 genes in a severe developmental disorder cohort, including 123 novel candidates. These genes are functionally similar to known disease genes, and their variants often localize to critical regions. Remarkably, popEVE can prioritize likely causal variants using only child exomes, enabling diagnosis even without parental sequencing. This work provides a generalizable framework for rare disease variant interpretation, especially in singleton cases, and demonstrates the utility of calibrated, evolution-informed scoring models for clinical genomics. popEVE is a proteome-wide deep generative model to identify and predict pathogenicity of missense mutations causing genetic disorders.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 12","pages":"3165-3174"},"PeriodicalIF":29.0,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-025-02400-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145583025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-20DOI: 10.1038/s41588-025-02403-y
Eunjae Park, Kisung Nam, Seokho Jeong, Karl Keat, Dokyoon Kim, Vikas Bansal, Wei Zhou, Seunggeun Lee
Meta-analysis enhances the power of rare variant association tests by combining summary statistics across several cohorts. However, existing methods often fail to control type I error for low-prevalence binary traits and are computationally intensive. Here we introduce Meta-SAIGE—a scalable method for rare variant meta-analysis that accurately estimates the null distribution to control type I error and reuses the linkage disequilibrium matrix across phenotypes to boost computational efficiency in phenome-wide analyses. Simulations using UK Biobank whole-exome sequencing data show that Meta-SAIGE effectively controls type I error and achieves power comparable to pooled individual-level analysis with SAIGE-GENE+. Applying Meta-SAIGE to 83 low-prevalence phenotypes in UK Biobank and All of Us whole-exome sequencing data identified 237 gene–trait associations. Notably, 80 of these associations were not significant in either dataset alone, underscoring the power of our meta-analysis. Meta-SAIGE is a computationally efficient method for meta-analysis of rare variant associations across cohorts. It effectively controls type I error rates and has power similar to analyses of pooled individual-level data.
荟萃分析通过结合多个队列的汇总统计数据来增强罕见变异关联检验的有效性。然而，现有的方法往往不能控制低流行率二元特征的I型误差，并且计算量大。在这里，我们引入meta- saige——一种用于罕见变异荟萃分析的可扩展方法，它可以准确地估计零分布以控制I型误差，并重用跨表型的连锁不平衡矩阵来提高全表型分析的计算效率。使用UK Biobank全外显子组测序数据的模拟表明，Meta-SAIGE有效地控制了I型误差，并达到了与SAIGE-GENE+的汇总个人水平分析相当的能力。将meta - sage应用于UK Biobank和All of Us中的83种低患病率表型，确定了237种基因性状关联。值得注意的是，其中80个关联在单独的两个数据集中都不显著，强调了我们的荟萃分析的力量。meta- sage是一种计算效率高的方法，用于跨队列的罕见变异关联的荟萃分析。它有效地控制了I类错误率，并且具有类似于汇总个人级别数据的分析的能力。
{"title":"Scalable and accurate rare variant meta-analysis with Meta-SAIGE","authors":"Eunjae Park, Kisung Nam, Seokho Jeong, Karl Keat, Dokyoon Kim, Vikas Bansal, Wei Zhou, Seunggeun Lee","doi":"10.1038/s41588-025-02403-y","DOIUrl":"10.1038/s41588-025-02403-y","url":null,"abstract":"Meta-analysis enhances the power of rare variant association tests by combining summary statistics across several cohorts. However, existing methods often fail to control type I error for low-prevalence binary traits and are computationally intensive. Here we introduce Meta-SAIGE—a scalable method for rare variant meta-analysis that accurately estimates the null distribution to control type I error and reuses the linkage disequilibrium matrix across phenotypes to boost computational efficiency in phenome-wide analyses. Simulations using UK Biobank whole-exome sequencing data show that Meta-SAIGE effectively controls type I error and achieves power comparable to pooled individual-level analysis with SAIGE-GENE+. Applying Meta-SAIGE to 83 low-prevalence phenotypes in UK Biobank and All of Us whole-exome sequencing data identified 237 gene–trait associations. Notably, 80 of these associations were not significant in either dataset alone, underscoring the power of our meta-analysis. Meta-SAIGE is a computationally efficient method for meta-analysis of rare variant associations across cohorts. It effectively controls type I error rates and has power similar to analyses of pooled individual-level data.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 12","pages":"3185-3192"},"PeriodicalIF":29.0,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-025-02403-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145554412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-19DOI: 10.1038/s41588-025-02422-9
We establish that adenine DNA methylation is widespread among unicellular eukaryotes, in which it marks transcriptionally active genes. This conserved pattern depends on the AMT1 enzyme, an ancestral eukaryotic adenine methyltransferase that has been recurrently lost in multicellular lineages, such as animals and plants.
{"title":"Adenine DNA methylation is an ancestral and widespread mark in eukaryotes","authors":"","doi":"10.1038/s41588-025-02422-9","DOIUrl":"10.1038/s41588-025-02422-9","url":null,"abstract":"We establish that adenine DNA methylation is widespread among unicellular eukaryotes, in which it marks transcriptionally active genes. This conserved pattern depends on the AMT1 enzyme, an ancestral eukaryotic adenine methyltransferase that has been recurrently lost in multicellular lineages, such as animals and plants.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 12","pages":"2960-2961"},"PeriodicalIF":29.0,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145545468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-18DOI: 10.1038/s41588-025-02404-x
Takeo Narita, Sinan Kilic, Yoshiki Higashijima, Natalie M. Scherer, Georgios Pappas, Elina Maskey, Chunaram Choudhary
Cohesin- and CTCF-mediated chromatin loops facilitate enhancer–promoter and promoter–promoter interactions, but their impact on global gene regulation remains debated. Here we show that acute removal of cohesin or CTCF in mouse cells dysregulates hundreds of genes. Cohesin depletion primarily downregulates CBP/p300-dependent putative enhancer targets, whereas CTCF loss both up- and downregulates enhancer targets. Beyond loop anchoring, CTCF directly modulates transcription, acting as an activator or repressor depending on its binding position and orientation at promoters. Mechanistically, when activating, CTCF increases DNA accessibility and promotes RNA polymerase II recruitment; when repressing, it prevents RNA polymerase II binding without altering chromatin accessibility. Promoter-bound CTCF activates housekeeping genes essential for cell proliferation. CTCF’s transcriptional activation function—but not its loop anchoring role—is shared with its vertebrate-specific paralog, CTCFL. These findings reconcile architectural and non-architectural roles of cohesin and CTCF, offering a unified model for their functions in enhancer-dependent and enhancer-independent transcription control. This study provides insights into the chromatin-looping-dependent and chromatin-looping-independent roles of cohesin and CTCF in controlling gene regulation.
{"title":"Disentangling the architectural and non-architectural functions of CTCF and cohesin in gene regulation","authors":"Takeo Narita, Sinan Kilic, Yoshiki Higashijima, Natalie M. Scherer, Georgios Pappas, Elina Maskey, Chunaram Choudhary","doi":"10.1038/s41588-025-02404-x","DOIUrl":"10.1038/s41588-025-02404-x","url":null,"abstract":"Cohesin- and CTCF-mediated chromatin loops facilitate enhancer–promoter and promoter–promoter interactions, but their impact on global gene regulation remains debated. Here we show that acute removal of cohesin or CTCF in mouse cells dysregulates hundreds of genes. Cohesin depletion primarily downregulates CBP/p300-dependent putative enhancer targets, whereas CTCF loss both up- and downregulates enhancer targets. Beyond loop anchoring, CTCF directly modulates transcription, acting as an activator or repressor depending on its binding position and orientation at promoters. Mechanistically, when activating, CTCF increases DNA accessibility and promotes RNA polymerase II recruitment; when repressing, it prevents RNA polymerase II binding without altering chromatin accessibility. Promoter-bound CTCF activates housekeeping genes essential for cell proliferation. CTCF’s transcriptional activation function—but not its loop anchoring role—is shared with its vertebrate-specific paralog, CTCFL. These findings reconcile architectural and non-architectural roles of cohesin and CTCF, offering a unified model for their functions in enhancer-dependent and enhancer-independent transcription control. This study provides insights into the chromatin-looping-dependent and chromatin-looping-independent roles of cohesin and CTCF in controlling gene regulation.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 12","pages":"3137-3151"},"PeriodicalIF":29.0,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-025-02404-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145536175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-18DOI: 10.1038/s41588-025-02409-6
Pedro Romero Charria, Cristina Navarrete, Vladimir Ovchinnikov, Lan Xu, Luke A. Sarre, Victoria Shabardina, Ewa Ksiezopolska, Elena Casacuberta, David Lara-Astiaso, Arnau Sebé-Pedrós, Alex de Mendoza
DNA methylation is a key regulator of eukaryotic genomes, most commonly through 5-methylcytosine (5mC). In contrast, the existence and function of N6-methyladenine (6mA) in eukaryotes have been controversial, with conflicting reports resulting from methodological artifacts. Nevertheless, some unicellular lineages, including ciliates, early-branching fungi and the alga Chlamydomonas, show robust 6mA signals, raising questions about their origin and evolutionary role. Here we apply Oxford Nanopore sequencing to profile 6mA at base-pair resolution across 18 unicellular eukaryotes representing all major supergroups. We find that robust 6mA patterns occur only in species that encode the adenine methyltransferase AMT1. Notably, 6mA consistently accumulates downstream of transcriptional start sites, positioned between H3K4me3-marked nucleosomes, indicating a conserved association with transcriptional activation. Our results support the idea that the last eukaryotic common ancestor had a dual methylation system, with transcription-linked 6mA and repressive 5mC, which has been repeatedly simplified in both multicellular and unicellular lineages through the loss of the AMT1 pathway. Long-read sequencing in 18 unicellular eukaryotes reveals that 6mA is widespread across eukaryotes and is enriched at transcriptionally permissive regions, which are also marked by H3K4me3.
{"title":"Adenine DNA methylation associated with transcriptionally permissive chromatin is widespread across eukaryotes","authors":"Pedro Romero Charria, Cristina Navarrete, Vladimir Ovchinnikov, Lan Xu, Luke A. Sarre, Victoria Shabardina, Ewa Ksiezopolska, Elena Casacuberta, David Lara-Astiaso, Arnau Sebé-Pedrós, Alex de Mendoza","doi":"10.1038/s41588-025-02409-6","DOIUrl":"10.1038/s41588-025-02409-6","url":null,"abstract":"DNA methylation is a key regulator of eukaryotic genomes, most commonly through 5-methylcytosine (5mC). In contrast, the existence and function of N6-methyladenine (6mA) in eukaryotes have been controversial, with conflicting reports resulting from methodological artifacts. Nevertheless, some unicellular lineages, including ciliates, early-branching fungi and the alga Chlamydomonas, show robust 6mA signals, raising questions about their origin and evolutionary role. Here we apply Oxford Nanopore sequencing to profile 6mA at base-pair resolution across 18 unicellular eukaryotes representing all major supergroups. We find that robust 6mA patterns occur only in species that encode the adenine methyltransferase AMT1. Notably, 6mA consistently accumulates downstream of transcriptional start sites, positioned between H3K4me3-marked nucleosomes, indicating a conserved association with transcriptional activation. Our results support the idea that the last eukaryotic common ancestor had a dual methylation system, with transcription-linked 6mA and repressive 5mC, which has been repeatedly simplified in both multicellular and unicellular lineages through the loss of the AMT1 pathway. Long-read sequencing in 18 unicellular eukaryotes reveals that 6mA is widespread across eukaryotes and is enriched at transcriptionally permissive regions, which are also marked by H3K4me3.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 12","pages":"3126-3136"},"PeriodicalIF":29.0,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-025-02409-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145536192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-17DOI: 10.1038/s41588-025-02398-6
Gudny Ella Thorlacius, Erna V. Ivarsdottir, Saedis Saevarsdottir, Kristjan H. S. Moore, Sigurjon A. Gudjonsson, Bjarni V. Halldorsson, Hilma Holm, Aslaug Jonasdottir, Frosti Jonsson, Snaedis Kristmundsdottir, Gisli Masson, Olafur T. Magnusson, Gudmundur L. Norddahl, Asmundur Oddsson, Thorunn A. Olafsdottir, Pall I. Olason, Aron Skaftason, Lilja Stefansdottir, Arni Sturluson, Unnur Thorsteinsdottir, Gudmar Thorleifsson, Valentin Y. Walker, Florian Zink, Eirikur Steingrimsson, Daniel F. Gudbjartsson, Ingileif Jonsdottir, Agnar Helgason, Patrick Sulem, Kari Stefansson
Cutaneous lupus erythematosus (CLE) is an autoimmune disease of the skin, occurring with or without systemic lupus erythematosus (SLE). People with African ancestry have a higher risk than people with other ancestries of developing lupus1 but have been underrepresented in genetic studies. We whole-genome-sequenced 27,820 Americans with genetically inferred African ancestry from the Diverse Ancestry Cohort, including people with CLE (n = 211) and/or SLE (n = 574). We discovered an association with a rare missense variant in IKBKB, rs115698972G>A, IKKβE502K, exclusive to people with African ancestry, conferring an odds ratio (OR) of 5.4 for CLE and 3.3 for SLE. These associations replicated in the All of Us and VA Million Veteran Research Programs for CLE (ORmeta = 3.8, Pmeta = 5.3 × 10−20, n = 1,243) and SLE (ORmeta = 3.2, Pmeta = 1.0 × 10−19, n = 1,697). In this cohort, IKKβE502K accounts for 10.4% of CLE cases and 6.4% of SLE cases, confers a high lupus risk, and contributes substantially to the disease prevalence among people with African ancestry. This highlights the value of including diverse ancestries in genetic association studies. Whole-genome sequencing identifies a rare missense variant in IKBKB associated with high risk of cutaneous and systemic lupus erythematosus among people with African ancestry.
{"title":"African-ancestry-specific variant IKKβ p.Glu502Lys confers high lupus risk","authors":"Gudny Ella Thorlacius, Erna V. Ivarsdottir, Saedis Saevarsdottir, Kristjan H. S. Moore, Sigurjon A. Gudjonsson, Bjarni V. Halldorsson, Hilma Holm, Aslaug Jonasdottir, Frosti Jonsson, Snaedis Kristmundsdottir, Gisli Masson, Olafur T. Magnusson, Gudmundur L. Norddahl, Asmundur Oddsson, Thorunn A. Olafsdottir, Pall I. Olason, Aron Skaftason, Lilja Stefansdottir, Arni Sturluson, Unnur Thorsteinsdottir, Gudmar Thorleifsson, Valentin Y. Walker, Florian Zink, Eirikur Steingrimsson, Daniel F. Gudbjartsson, Ingileif Jonsdottir, Agnar Helgason, Patrick Sulem, Kari Stefansson","doi":"10.1038/s41588-025-02398-6","DOIUrl":"10.1038/s41588-025-02398-6","url":null,"abstract":"Cutaneous lupus erythematosus (CLE) is an autoimmune disease of the skin, occurring with or without systemic lupus erythematosus (SLE). People with African ancestry have a higher risk than people with other ancestries of developing lupus1 but have been underrepresented in genetic studies. We whole-genome-sequenced 27,820 Americans with genetically inferred African ancestry from the Diverse Ancestry Cohort, including people with CLE (n = 211) and/or SLE (n = 574). We discovered an association with a rare missense variant in IKBKB, rs115698972G>A, IKKβE502K, exclusive to people with African ancestry, conferring an odds ratio (OR) of 5.4 for CLE and 3.3 for SLE. These associations replicated in the All of Us and VA Million Veteran Research Programs for CLE (ORmeta = 3.8, Pmeta = 5.3 × 10−20, n = 1,243) and SLE (ORmeta = 3.2, Pmeta = 1.0 × 10−19, n = 1,697). In this cohort, IKKβE502K accounts for 10.4% of CLE cases and 6.4% of SLE cases, confers a high lupus risk, and contributes substantially to the disease prevalence among people with African ancestry. This highlights the value of including diverse ancestries in genetic association studies. Whole-genome sequencing identifies a rare missense variant in IKBKB associated with high risk of cutaneous and systemic lupus erythematosus among people with African ancestry.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 12","pages":"2980-2986"},"PeriodicalIF":29.0,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41588-025-02398-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145531627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-14DOI: 10.1038/s41588-025-02379-9
Our study reveals how transforming growth factor-β (TGFβ) enables liver metastasis of colorectal cancer (CRC) in two ways: by limiting CD8⁺ T cell recruitment and inducing SPP1⁺ macrophages. Inhibition of TGFβ sensitizes tumors to PD-L1 blockade therapy, eradicating metastases in different CRC genetic models. Targeting SPP1 offers therapeutic benefit while avoiding the systemic effects of complete TGFβ inhibition.
{"title":"Two-pronged immunosuppression by TGFβ supports colorectal cancer metastasis","authors":"","doi":"10.1038/s41588-025-02379-9","DOIUrl":"10.1038/s41588-025-02379-9","url":null,"abstract":"Our study reveals how transforming growth factor-β (TGFβ) enables liver metastasis of colorectal cancer (CRC) in two ways: by limiting CD8⁺ T cell recruitment and inducing SPP1⁺ macrophages. Inhibition of TGFβ sensitizes tumors to PD-L1 blockade therapy, eradicating metastases in different CRC genetic models. Targeting SPP1 offers therapeutic benefit while avoiding the systemic effects of complete TGFβ inhibition.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 12","pages":"2956-2957"},"PeriodicalIF":29.0,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145515548","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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