Pub Date : 2024-09-03DOI: 10.1038/s41588-024-01874-9
Peiran Su, Yin Liu, Tianyi Chen, Yibo Xue, Yong Zeng, Guanghui Zhu, Sujun Chen, Mona Teng, Xinpei Ci, Mengdi Guo, Michael Y. He, Jun Hao, Vivian Chu, Wenxi Xu, Shiyan Wang, Parinaz Mehdipour, Xin Xu, Sajid A. Marhon, Fraser Soares, Nhu-An Pham, Bell Xi Wu, Peter Hyunwuk Her, Shengrui Feng, Najd Alshamlan, Maryam Khalil, Rehna Krishnan, Fangyou Yu, Chang Chen, Francis Burrows, Razqallah Hakem, Mathieu Lupien, Shane Harding, Benjamin H. Lok, Catherine O’Brien, Alejandro Berlin, Daniel D. De Carvalho, David G. Brooks, Daniel Schramek, Ming-Sound Tsao, Housheng Hansen He
Functional genomic screens in two-dimensional cell culture models are limited in identifying therapeutic targets that influence the tumor microenvironment. By comparing targeted CRISPR–Cas9 screens in a two-dimensional culture with xenografts derived from the same cell line, we identified MEN1 as the top hit that confers differential dropout effects in vitro and in vivo. MEN1 knockout in multiple solid cancer types does not impact cell proliferation in vitro but significantly promotes or inhibits tumor growth in immunodeficient or immunocompetent mice, respectively. Mechanistically, MEN1 knockout redistributes MLL1 chromatin occupancy, increasing H3K4me3 at repetitive genomic regions, activating double-stranded RNA expression and increasing neutrophil and CD8+ T cell infiltration in immunodeficient and immunocompetent mice, respectively. Pharmacological inhibition of the menin–MLL interaction reduces tumor growth in a CD8+ T cell-dependent manner. These findings reveal tumor microenvironment-dependent oncogenic and tumor-suppressive functions of MEN1 and provide a rationale for targeting MEN1 in solid cancers. Loss of MEN1 affects tumor growth, varing with the components of the tumor microenvironment. These tumors show redistribution of MLL1 on chromatin and the activation of a viral mimicry response.
{"title":"In vivo CRISPR screens identify a dual function of MEN1 in regulating tumor–microenvironment interactions","authors":"Peiran Su, Yin Liu, Tianyi Chen, Yibo Xue, Yong Zeng, Guanghui Zhu, Sujun Chen, Mona Teng, Xinpei Ci, Mengdi Guo, Michael Y. He, Jun Hao, Vivian Chu, Wenxi Xu, Shiyan Wang, Parinaz Mehdipour, Xin Xu, Sajid A. Marhon, Fraser Soares, Nhu-An Pham, Bell Xi Wu, Peter Hyunwuk Her, Shengrui Feng, Najd Alshamlan, Maryam Khalil, Rehna Krishnan, Fangyou Yu, Chang Chen, Francis Burrows, Razqallah Hakem, Mathieu Lupien, Shane Harding, Benjamin H. Lok, Catherine O’Brien, Alejandro Berlin, Daniel D. De Carvalho, David G. Brooks, Daniel Schramek, Ming-Sound Tsao, Housheng Hansen He","doi":"10.1038/s41588-024-01874-9","DOIUrl":"10.1038/s41588-024-01874-9","url":null,"abstract":"Functional genomic screens in two-dimensional cell culture models are limited in identifying therapeutic targets that influence the tumor microenvironment. By comparing targeted CRISPR–Cas9 screens in a two-dimensional culture with xenografts derived from the same cell line, we identified MEN1 as the top hit that confers differential dropout effects in vitro and in vivo. MEN1 knockout in multiple solid cancer types does not impact cell proliferation in vitro but significantly promotes or inhibits tumor growth in immunodeficient or immunocompetent mice, respectively. Mechanistically, MEN1 knockout redistributes MLL1 chromatin occupancy, increasing H3K4me3 at repetitive genomic regions, activating double-stranded RNA expression and increasing neutrophil and CD8+ T cell infiltration in immunodeficient and immunocompetent mice, respectively. Pharmacological inhibition of the menin–MLL interaction reduces tumor growth in a CD8+ T cell-dependent manner. These findings reveal tumor microenvironment-dependent oncogenic and tumor-suppressive functions of MEN1 and provide a rationale for targeting MEN1 in solid cancers. Loss of MEN1 affects tumor growth, varing with the components of the tumor microenvironment. These tumors show redistribution of MLL1 on chromatin and the activation of a viral mimicry response.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 9","pages":"1890-1902"},"PeriodicalIF":31.7,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01874-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142123704","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 : 2024-09-03DOI: 10.1038/s41588-024-01890-9
Carina Shiau, Jingyi Cao, Dennis Gong, Mark T. Gregory, Nicholas J. Caldwell, Xunqin Yin, Jae-Won Cho, Peter L. Wang, Jennifer Su, Steven Wang, Jason W. Reeves, Tae Kyung Kim, Youngmi Kim, Jimmy A. Guo, Nicole A. Lester, Jung Woo Bae, Ryan Zhao, Nathan Schurman, Jamie L. Barth, Maria L. Ganci, Ralph Weissleder, Tyler Jacks, Motaz Qadan, Theodore S. Hong, Jennifer Y. Wo, Hannah Roberts, Joseph M. Beechem, Carlos Fernandez-del Castillo, Mari Mino-Kenudson, David T. Ting, Martin Hemberg, William L. Hwang
In combination with cell-intrinsic properties, interactions in the tumor microenvironment modulate therapeutic response. We leveraged single-cell spatial transcriptomics to dissect the remodeling of multicellular neighborhoods and cell–cell interactions in human pancreatic cancer associated with neoadjuvant chemotherapy and radiotherapy. We developed spatially constrained optimal transport interaction analysis (SCOTIA), an optimal transport model with a cost function that includes both spatial distance and ligand–receptor gene expression. Our results uncovered a marked change in ligand–receptor interactions between cancer-associated fibroblasts and malignant cells in response to treatment, which was supported by orthogonal datasets, including an ex vivo tumoroid coculture system. We identified enrichment in interleukin-6 family signaling that functionally confers resistance to chemotherapy. Overall, this study demonstrates that characterization of the tumor microenvironment using single-cell spatial transcriptomics allows for the identification of molecular interactions that may play a role in the emergence of therapeutic resistance and offers a spatially based analysis framework that can be broadly applied to other contexts. Spatial molecular imaging analysis of human pancreatic adenocarcinomas describes multicellular neighborhoods in the tumor microenvironment. Ligand–receptor analysis using optimal transport-based SCOTIA identifies interleukin-6 as a mediator of chemoresistance.
{"title":"Spatially resolved analysis of pancreatic cancer identifies therapy-associated remodeling of the tumor microenvironment","authors":"Carina Shiau, Jingyi Cao, Dennis Gong, Mark T. Gregory, Nicholas J. Caldwell, Xunqin Yin, Jae-Won Cho, Peter L. Wang, Jennifer Su, Steven Wang, Jason W. Reeves, Tae Kyung Kim, Youngmi Kim, Jimmy A. Guo, Nicole A. Lester, Jung Woo Bae, Ryan Zhao, Nathan Schurman, Jamie L. Barth, Maria L. Ganci, Ralph Weissleder, Tyler Jacks, Motaz Qadan, Theodore S. Hong, Jennifer Y. Wo, Hannah Roberts, Joseph M. Beechem, Carlos Fernandez-del Castillo, Mari Mino-Kenudson, David T. Ting, Martin Hemberg, William L. Hwang","doi":"10.1038/s41588-024-01890-9","DOIUrl":"10.1038/s41588-024-01890-9","url":null,"abstract":"In combination with cell-intrinsic properties, interactions in the tumor microenvironment modulate therapeutic response. We leveraged single-cell spatial transcriptomics to dissect the remodeling of multicellular neighborhoods and cell–cell interactions in human pancreatic cancer associated with neoadjuvant chemotherapy and radiotherapy. We developed spatially constrained optimal transport interaction analysis (SCOTIA), an optimal transport model with a cost function that includes both spatial distance and ligand–receptor gene expression. Our results uncovered a marked change in ligand–receptor interactions between cancer-associated fibroblasts and malignant cells in response to treatment, which was supported by orthogonal datasets, including an ex vivo tumoroid coculture system. We identified enrichment in interleukin-6 family signaling that functionally confers resistance to chemotherapy. Overall, this study demonstrates that characterization of the tumor microenvironment using single-cell spatial transcriptomics allows for the identification of molecular interactions that may play a role in the emergence of therapeutic resistance and offers a spatially based analysis framework that can be broadly applied to other contexts. Spatial molecular imaging analysis of human pancreatic adenocarcinomas describes multicellular neighborhoods in the tumor microenvironment. Ligand–receptor analysis using optimal transport-based SCOTIA identifies interleukin-6 as a mediator of chemoresistance.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 11","pages":"2466-2478"},"PeriodicalIF":31.7,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142123705","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 : 2024-09-02DOI: 10.1038/s41588-024-01850-3
Darwin W. Kwok, Hideho Okada, Joseph F. Costello
Epigenetic therapy triggers myriad transposable elements to generate new antigens that could prime tumor cells for immunotherapy. A study of glioblastoma discovers indiscriminate activation in healthy cells as well, and presents a more selective strategy for potential therapeutic targeting.
{"title":"Activating the dark genome to illuminate cancer vaccine targets","authors":"Darwin W. Kwok, Hideho Okada, Joseph F. Costello","doi":"10.1038/s41588-024-01850-3","DOIUrl":"10.1038/s41588-024-01850-3","url":null,"abstract":"Epigenetic therapy triggers myriad transposable elements to generate new antigens that could prime tumor cells for immunotherapy. A study of glioblastoma discovers indiscriminate activation in healthy cells as well, and presents a more selective strategy for potential therapeutic targeting.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 9","pages":"1770-1771"},"PeriodicalIF":31.7,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142118127","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 : 2024-09-02DOI: 10.1038/s41588-024-01872-x
Benjamin Fair, Carlos F. Buen Abad Najar, Junxing Zhao, Stephanie Lozano, Austin Reilly, Gabriela Mossian, Jonathan P. Staley, Jingxin Wang, Yang I. Li
Alternative splicing (AS) in human genes is widely viewed as a mechanism for enhancing proteomic diversity. AS can also impact gene expression levels without increasing protein diversity by producing ‘unproductive’ transcripts that are targeted for rapid degradation by nonsense-mediated decay (NMD). However, the relative importance of this regulatory mechanism remains underexplored. To better understand the impact of AS–NMD relative to other regulatory mechanisms, we analyzed population-scale genomic data across eight molecular assays, covering various stages from transcription to cytoplasmic decay. We report threefold more unproductive splicing compared with prior estimates using steady-state RNA. This unproductive splicing compounds across multi-intronic genes, resulting in 15% of transcript molecules from protein-coding genes being unproductive. Leveraging genetic variation across cell lines, we find that GWAS trait-associated loci explained by AS are as often associated with NMD-induced expression level differences as with differences in protein isoform usage. Our findings suggest that much of the impact of AS is mediated by NMD-induced changes in gene expression rather than diversification of the proteome. Genomic analyses suggest that ~15% of transcript molecules are spliced into unproductive transcripts targeted by nonsense-mediated decay, which have a larger effect on gene expression than previously thought.
{"title":"Global impact of unproductive splicing on human gene expression","authors":"Benjamin Fair, Carlos F. Buen Abad Najar, Junxing Zhao, Stephanie Lozano, Austin Reilly, Gabriela Mossian, Jonathan P. Staley, Jingxin Wang, Yang I. Li","doi":"10.1038/s41588-024-01872-x","DOIUrl":"10.1038/s41588-024-01872-x","url":null,"abstract":"Alternative splicing (AS) in human genes is widely viewed as a mechanism for enhancing proteomic diversity. AS can also impact gene expression levels without increasing protein diversity by producing ‘unproductive’ transcripts that are targeted for rapid degradation by nonsense-mediated decay (NMD). However, the relative importance of this regulatory mechanism remains underexplored. To better understand the impact of AS–NMD relative to other regulatory mechanisms, we analyzed population-scale genomic data across eight molecular assays, covering various stages from transcription to cytoplasmic decay. We report threefold more unproductive splicing compared with prior estimates using steady-state RNA. This unproductive splicing compounds across multi-intronic genes, resulting in 15% of transcript molecules from protein-coding genes being unproductive. Leveraging genetic variation across cell lines, we find that GWAS trait-associated loci explained by AS are as often associated with NMD-induced expression level differences as with differences in protein isoform usage. Our findings suggest that much of the impact of AS is mediated by NMD-induced changes in gene expression rather than diversification of the proteome. Genomic analyses suggest that ~15% of transcript molecules are spliced into unproductive transcripts targeted by nonsense-mediated decay, which have a larger effect on gene expression than previously thought.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 9","pages":"1851-1861"},"PeriodicalIF":31.7,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01872-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142118130","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 : 2024-09-02DOI: 10.1038/s41588-024-01880-x
H. Josh Jang, Nakul M. Shah, Ju Heon Maeng, Yonghao Liang, Noah L. Basri, Jiaxin Ge, Xuan Qu, Tatenda Mahlokozera, Shin-Cheng Tzeng, Russell B. Williams, Michael J. Moore, Devi Annamalai, Justin Y. Chen, Hyung Joo Lee, Patrick A. DeSouza, Daofeng Li, Xiaoyun Xing, Albert H. Kim, Ting Wang
Inhibiting epigenetic modulators can transcriptionally reactivate transposable elements (TEs). These TE transcripts often generate unique peptides that can serve as immunogenic antigens for immunotherapy. Here, we ask whether TEs activated by epigenetic therapy could appreciably increase the antigen repertoire in glioblastoma, an aggressive brain cancer with low mutation and neoantigen burden. We treated patient-derived primary glioblastoma stem cell lines, an astrocyte cell line and primary fibroblast cell lines with epigenetic drugs, and identified treatment-induced, TE-derived transcripts that are preferentially expressed in cancer cells. We verified that these transcripts could produce human leukocyte antigen class I-presented antigens using liquid chromatography with tandem mass spectrometry pulldown experiments. Importantly, many TEs were also transcribed, even in proliferating nontumor cell lines, after epigenetic therapy, which suggests that targeted strategies like CRISPR-mediated activation could minimize potential side effects of activating unwanted genomic regions. The results highlight both the need for caution and the promise of future translational efforts in harnessing treatment-induced TE-derived antigens for targeted immunotherapy. Treatment of primary glioblastoma cell lines with epigenetic therapy reactivates transposable elements (TEs). TE-derived transcripts can produce human leukocyte antigen class I-presented antigens, which could potentially be therapeutically targeted.
抑制表观遗传调节剂可以转录重新激活转座元件（TE）。这些TE转录本通常会产生独特的多肽，可作为免疫疗法的免疫原性抗原。胶质母细胞瘤是一种侵袭性脑癌，其突变和新抗原负担较低。我们用表观遗传学药物处理了源自患者的原代胶质母细胞瘤干细胞系、星形胶质细胞系和原代成纤维细胞系，并确定了治疗诱导的、在癌细胞中优先表达的 TE 衍生转录本。我们利用液相色谱-串联质谱下拉实验验证了这些转录本能产生人类白细胞抗原 I 类呈递抗原。重要的是，在表观遗传学治疗后，许多 TEs 也被转录，甚至在增殖的非肿瘤细胞系中也是如此，这表明 CRISPR 介导的激活等靶向策略可以最大限度地减少激活不需要的基因组区域的潜在副作用。这些结果凸显了利用治疗诱导的 TE 衍生抗原进行靶向免疫疗法的谨慎性和未来转化工作的前景。
{"title":"Epigenetic therapy potentiates transposable element transcription to create tumor-enriched antigens in glioblastoma cells","authors":"H. Josh Jang, Nakul M. Shah, Ju Heon Maeng, Yonghao Liang, Noah L. Basri, Jiaxin Ge, Xuan Qu, Tatenda Mahlokozera, Shin-Cheng Tzeng, Russell B. Williams, Michael J. Moore, Devi Annamalai, Justin Y. Chen, Hyung Joo Lee, Patrick A. DeSouza, Daofeng Li, Xiaoyun Xing, Albert H. Kim, Ting Wang","doi":"10.1038/s41588-024-01880-x","DOIUrl":"10.1038/s41588-024-01880-x","url":null,"abstract":"Inhibiting epigenetic modulators can transcriptionally reactivate transposable elements (TEs). These TE transcripts often generate unique peptides that can serve as immunogenic antigens for immunotherapy. Here, we ask whether TEs activated by epigenetic therapy could appreciably increase the antigen repertoire in glioblastoma, an aggressive brain cancer with low mutation and neoantigen burden. We treated patient-derived primary glioblastoma stem cell lines, an astrocyte cell line and primary fibroblast cell lines with epigenetic drugs, and identified treatment-induced, TE-derived transcripts that are preferentially expressed in cancer cells. We verified that these transcripts could produce human leukocyte antigen class I-presented antigens using liquid chromatography with tandem mass spectrometry pulldown experiments. Importantly, many TEs were also transcribed, even in proliferating nontumor cell lines, after epigenetic therapy, which suggests that targeted strategies like CRISPR-mediated activation could minimize potential side effects of activating unwanted genomic regions. The results highlight both the need for caution and the promise of future translational efforts in harnessing treatment-induced TE-derived antigens for targeted immunotherapy. Treatment of primary glioblastoma cell lines with epigenetic therapy reactivates transposable elements (TEs). TE-derived transcripts can produce human leukocyte antigen class I-presented antigens, which could potentially be therapeutically targeted.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 9","pages":"1903-1913"},"PeriodicalIF":31.7,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142118131","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 : 2024-08-29DOI: 10.1038/s41588-024-01871-y
Jessica C. Lam, Nicholas G. Aboreden, Susannah C. Midla, Siqing Wang, Anran Huang, Cheryl A. Keller, Belinda Giardine, Kate A. Henderson, Ross C. Hardison, Haoyue Zhang, Gerd A. Blobel
Few transcription factors have been examined for their direct roles in physically connecting enhancers and promoters. Here acute degradation of Yin Yang 1 (YY1) in erythroid cells revealed its requirement for the maintenance of numerous enhancer–promoter loops, but not compartments or domains. Despite its reported ability to interact with cohesin, the formation of YY1-dependent enhancer–promoter loops does not involve stalling of cohesin-mediated loop extrusion. Integrating mitosis-to-G1-phase dynamics, we observed partial retention of YY1 on mitotic chromatin, predominantly at gene promoters, followed by rapid rebinding during mitotic exit, coinciding with enhancer–promoter loop establishment. YY1 degradation during the mitosis-to-G1-phase interval revealed a set of enhancer–promoter loops that require YY1 for establishment during G1-phase entry but not for maintenance in interphase, suggesting that cell cycle stage influences YY1’s architectural function. Thus, as revealed here for YY1, chromatin architectural functions of transcription factors can vary in their interplay with CTCF and cohesin as well as by cell cycle stage. Yin Yang 1 (YY1) aids in the formation of enhancer–promoter (E–P) loops independently of cohesin. YY1 maintains a subset of E–P interactions in interphase and establishes an overlapping yet distinct set after mitotic exit.
{"title":"YY1-controlled regulatory connectivity and transcription are influenced by the cell cycle","authors":"Jessica C. Lam, Nicholas G. Aboreden, Susannah C. Midla, Siqing Wang, Anran Huang, Cheryl A. Keller, Belinda Giardine, Kate A. Henderson, Ross C. Hardison, Haoyue Zhang, Gerd A. Blobel","doi":"10.1038/s41588-024-01871-y","DOIUrl":"10.1038/s41588-024-01871-y","url":null,"abstract":"Few transcription factors have been examined for their direct roles in physically connecting enhancers and promoters. Here acute degradation of Yin Yang 1 (YY1) in erythroid cells revealed its requirement for the maintenance of numerous enhancer–promoter loops, but not compartments or domains. Despite its reported ability to interact with cohesin, the formation of YY1-dependent enhancer–promoter loops does not involve stalling of cohesin-mediated loop extrusion. Integrating mitosis-to-G1-phase dynamics, we observed partial retention of YY1 on mitotic chromatin, predominantly at gene promoters, followed by rapid rebinding during mitotic exit, coinciding with enhancer–promoter loop establishment. YY1 degradation during the mitosis-to-G1-phase interval revealed a set of enhancer–promoter loops that require YY1 for establishment during G1-phase entry but not for maintenance in interphase, suggesting that cell cycle stage influences YY1’s architectural function. Thus, as revealed here for YY1, chromatin architectural functions of transcription factors can vary in their interplay with CTCF and cohesin as well as by cell cycle stage. Yin Yang 1 (YY1) aids in the formation of enhancer–promoter (E–P) loops independently of cohesin. YY1 maintains a subset of E–P interactions in interphase and establishes an overlapping yet distinct set after mitotic exit.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 9","pages":"1938-1952"},"PeriodicalIF":31.7,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142090008","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 : 2024-08-29DOI: 10.1038/s41588-024-01894-5
Sean J. Jurgens, Xin Wang, Seung Hoan Choi, Lu-Chen Weng, Satoshi Koyama, James P. Pirruccello, Trang Nguyen, Patrick Smadbeck, Dongkeun Jang, Mark Chaffin, Roddy Walsh, Carolina Roselli, Amanda L. Elliott, Leonoor F. J. M. Wijdeveld, Kiran J. Biddinger, Shinwan Kany, Joel T. Rämö, Pradeep Natarajan, Krishna G. Aragam, Jason Flannick, Noël P. Burtt, Connie R. Bezzina, Steven A. Lubitz, Kathryn L. Lunetta, Patrick T. Ellinor
Large-scale sequencing has enabled unparalleled opportunities to investigate the role of rare coding variation in human phenotypic variability. Here, we present a pan-ancestry analysis of sequencing data from three large biobanks, including the All of Us research program. Using mixed-effects models, we performed gene-based rare variant testing for 601 diseases across 748,879 individuals, including 155,236 with ancestry dissimilar to European. We identified 363 significant associations, which highlighted core genes for the human disease phenome and identified potential novel associations, including UBR3 for cardiometabolic disease and YLPM1 for psychiatric disease. Pan-ancestry burden testing represented an inclusive and useful approach for discovery in diverse datasets, although we also highlight the importance of ancestry-specific sensitivity analyses in this setting. Finally, we found that effect sizes for rare protein-disrupting variants were concordant between samples similar to European ancestry and other genetic ancestries (βDeming = 0.7–1.0). Our results have implications for multi-ancestry and cross-biobank approaches in sequencing association studies for human disease. Gene-based rare variant analyses for 601 diseases across 748,879 individuals from three biobanks identify 363 significant associations and highlight important considerations for multi-ancestry and cross-biobank sequencing studies.
{"title":"Rare coding variant analysis for human diseases across biobanks and ancestries","authors":"Sean J. Jurgens, Xin Wang, Seung Hoan Choi, Lu-Chen Weng, Satoshi Koyama, James P. Pirruccello, Trang Nguyen, Patrick Smadbeck, Dongkeun Jang, Mark Chaffin, Roddy Walsh, Carolina Roselli, Amanda L. Elliott, Leonoor F. J. M. Wijdeveld, Kiran J. Biddinger, Shinwan Kany, Joel T. Rämö, Pradeep Natarajan, Krishna G. Aragam, Jason Flannick, Noël P. Burtt, Connie R. Bezzina, Steven A. Lubitz, Kathryn L. Lunetta, Patrick T. Ellinor","doi":"10.1038/s41588-024-01894-5","DOIUrl":"10.1038/s41588-024-01894-5","url":null,"abstract":"Large-scale sequencing has enabled unparalleled opportunities to investigate the role of rare coding variation in human phenotypic variability. Here, we present a pan-ancestry analysis of sequencing data from three large biobanks, including the All of Us research program. Using mixed-effects models, we performed gene-based rare variant testing for 601 diseases across 748,879 individuals, including 155,236 with ancestry dissimilar to European. We identified 363 significant associations, which highlighted core genes for the human disease phenome and identified potential novel associations, including UBR3 for cardiometabolic disease and YLPM1 for psychiatric disease. Pan-ancestry burden testing represented an inclusive and useful approach for discovery in diverse datasets, although we also highlight the importance of ancestry-specific sensitivity analyses in this setting. Finally, we found that effect sizes for rare protein-disrupting variants were concordant between samples similar to European ancestry and other genetic ancestries (βDeming = 0.7–1.0). Our results have implications for multi-ancestry and cross-biobank approaches in sequencing association studies for human disease. Gene-based rare variant analyses for 601 diseases across 748,879 individuals from three biobanks identify 363 significant associations and highlight important considerations for multi-ancestry and cross-biobank sequencing studies.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 9","pages":"1811-1820"},"PeriodicalIF":31.7,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142090009","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 : 2024-08-28DOI: 10.1038/s41588-024-01873-w
Magda Marečková, Luz Garcia-Alonso, Marie Moullet, Valentina Lorenzi, Robert Petryszak, Carmen Sancho-Serra, Agnes Oszlanczi, Cecilia Icoresi Mazzeo, Frederick C. K. Wong, Iva Kelava, Sophie Hoffman, Michał Krassowski, Kurtis Garbutt, Kezia Gaitskell, Slaveya Yancheva, Ee Von Woon, Victoria Male, Ingrid Granne, Karin Hellner, Krishnaa T. Mahbubani, Kourosh Saeb-Parsy, Mohammad Lotfollahi, Elena Prigmore, Jennifer Southcombe, Rebecca A. Dragovic, Christian M. Becker, Krina T. Zondervan, Roser Vento-Tormo
The complex and dynamic cellular composition of the human endometrium remains poorly understood. Previous endometrial single-cell atlases profiled few donors and lacked consensus in defining cell types. We introduce the Human Endometrial Cell Atlas (HECA), a high-resolution single-cell reference atlas (313,527 cells) combining published and new endometrial single-cell transcriptomics datasets of 63 women with and without endometriosis. HECA assigns consensus and identifies previously unreported cell types, mapped in situ using spatial transcriptomics and validated using a new independent single-nuclei dataset (312,246 nuclei, 63 donors). In the functionalis, we identify intricate stromal–epithelial cell coordination via transforming growth factor beta (TGFβ) signaling. In the basalis, we define signaling between fibroblasts and an epithelial population expressing progenitor markers. Integration of HECA with large-scale endometriosis genome-wide association study data pinpoints decidualized stromal cells and macrophages as most likely dysregulated in endometriosis. The HECA is a valuable resource for studying endometrial physiology and disorders, and for guiding microphysiological in vitro systems development. The Human Endometrial Cell Atlas integrates single-cell transcriptomic datasets from women with and without endometriosis. Novel and known cell types are registered using spatial transcriptomics to provide a comprehensive map of the human endometrium in controls and endometriosis cases.
{"title":"An integrated single-cell reference atlas of the human endometrium","authors":"Magda Marečková, Luz Garcia-Alonso, Marie Moullet, Valentina Lorenzi, Robert Petryszak, Carmen Sancho-Serra, Agnes Oszlanczi, Cecilia Icoresi Mazzeo, Frederick C. K. Wong, Iva Kelava, Sophie Hoffman, Michał Krassowski, Kurtis Garbutt, Kezia Gaitskell, Slaveya Yancheva, Ee Von Woon, Victoria Male, Ingrid Granne, Karin Hellner, Krishnaa T. Mahbubani, Kourosh Saeb-Parsy, Mohammad Lotfollahi, Elena Prigmore, Jennifer Southcombe, Rebecca A. Dragovic, Christian M. Becker, Krina T. Zondervan, Roser Vento-Tormo","doi":"10.1038/s41588-024-01873-w","DOIUrl":"10.1038/s41588-024-01873-w","url":null,"abstract":"The complex and dynamic cellular composition of the human endometrium remains poorly understood. Previous endometrial single-cell atlases profiled few donors and lacked consensus in defining cell types. We introduce the Human Endometrial Cell Atlas (HECA), a high-resolution single-cell reference atlas (313,527 cells) combining published and new endometrial single-cell transcriptomics datasets of 63 women with and without endometriosis. HECA assigns consensus and identifies previously unreported cell types, mapped in situ using spatial transcriptomics and validated using a new independent single-nuclei dataset (312,246 nuclei, 63 donors). In the functionalis, we identify intricate stromal–epithelial cell coordination via transforming growth factor beta (TGFβ) signaling. In the basalis, we define signaling between fibroblasts and an epithelial population expressing progenitor markers. Integration of HECA with large-scale endometriosis genome-wide association study data pinpoints decidualized stromal cells and macrophages as most likely dysregulated in endometriosis. The HECA is a valuable resource for studying endometrial physiology and disorders, and for guiding microphysiological in vitro systems development. The Human Endometrial Cell Atlas integrates single-cell transcriptomic datasets from women with and without endometriosis. Novel and known cell types are registered using spatial transcriptomics to provide a comprehensive map of the human endometrium in controls and endometriosis cases.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 9","pages":"1925-1937"},"PeriodicalIF":31.7,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01873-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142084893","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 : 2024-08-27DOI: 10.1038/s41588-024-01885-6
Asmundur Oddsson, Valgerdur Steinthorsdottir, Gudjon R. Oskarsson, Unnur Styrkarsdottir, Kristjan H. S. Moore, Salvor Isberg, Gisli H. Halldorsson, Gardar Sveinbjornsson, David Westergaard, Henriette Svarre Nielsen, Run Fridriksdottir, Brynjar O. Jensson, Gudny A. Arnadottir, Hakon Jonsson, Arni Sturluson, Audunn S. Snaebjarnarson, Ole A. Andreassen, G. Bragi Walters, Mette Nyegaard, Christian Erikstrup, Thora Steingrimsdottir, Rolv T. Lie, Pall Melsted, Ingileif Jonsdottir, Bjarni V. Halldorsson, Gudmar Thorleifsson, Jona Saemundsdottir, Olafur Th. Magnusson, DBDS Genomic Consortium, Karina Banasik, Erik Sorensen, Gisli Masson, Ole Birger Pedersen, Laufey Tryggvadottir, Jan Haavik, Sisse Rye Ostrowski, Hreinn Stefansson, Hilma Holm, Thorunn Rafnar, Daniel F. Gudbjartsson, Patrick Sulem, Kari Stefansson
Age at menopause (AOM) has a substantial impact on fertility and disease risk. While many loci with variants that associate with AOM have been identified through genome-wide association studies (GWAS) under an additive model, other genetic models are rarely considered1. Here through GWAS meta-analysis under the recessive model of 174,329 postmenopausal women from Iceland, Denmark, the United Kingdom (UK; UK Biobank) and Norway, we study low-frequency variants with a large effect on AOM. We discovered that women homozygous for the stop-gain variant rs117316434 (A) in CCDC201 (p.(Arg162Ter), minor allele frequency ~1%) reached menopause 9 years earlier than other women (P = 1.3 × 10−15). The genotype is present in one in 10,000 northern European women and leads to primary ovarian insufficiency in close to half of them. Consequently, homozygotes have fewer children, and the age at last childbirth is 5 years earlier (P = 3.8 × 10−5). The CCDC201 gene was only found in humans in 2022 and is highly expressed in oocytes. Homozygosity for CCDC201 loss-of-function has a substantial impact on female reproductive health, and homozygotes would benefit from reproductive counseling and treatment for symptoms of early menopause. Genome-wide analysis of age at menopause under a recessive model identifies a stop-gain variant in CCDC201 associated with primary ovarian insufficiency. This homozygous genotype is present in 1 in 10,000 women of northern European ancestry.
{"title":"Homozygosity for a stop-gain variant in CCDC201 causes primary ovarian insufficiency","authors":"Asmundur Oddsson, Valgerdur Steinthorsdottir, Gudjon R. Oskarsson, Unnur Styrkarsdottir, Kristjan H. S. Moore, Salvor Isberg, Gisli H. Halldorsson, Gardar Sveinbjornsson, David Westergaard, Henriette Svarre Nielsen, Run Fridriksdottir, Brynjar O. Jensson, Gudny A. Arnadottir, Hakon Jonsson, Arni Sturluson, Audunn S. Snaebjarnarson, Ole A. Andreassen, G. Bragi Walters, Mette Nyegaard, Christian Erikstrup, Thora Steingrimsdottir, Rolv T. Lie, Pall Melsted, Ingileif Jonsdottir, Bjarni V. Halldorsson, Gudmar Thorleifsson, Jona Saemundsdottir, Olafur Th. Magnusson, DBDS Genomic Consortium, Karina Banasik, Erik Sorensen, Gisli Masson, Ole Birger Pedersen, Laufey Tryggvadottir, Jan Haavik, Sisse Rye Ostrowski, Hreinn Stefansson, Hilma Holm, Thorunn Rafnar, Daniel F. Gudbjartsson, Patrick Sulem, Kari Stefansson","doi":"10.1038/s41588-024-01885-6","DOIUrl":"10.1038/s41588-024-01885-6","url":null,"abstract":"Age at menopause (AOM) has a substantial impact on fertility and disease risk. While many loci with variants that associate with AOM have been identified through genome-wide association studies (GWAS) under an additive model, other genetic models are rarely considered1. Here through GWAS meta-analysis under the recessive model of 174,329 postmenopausal women from Iceland, Denmark, the United Kingdom (UK; UK Biobank) and Norway, we study low-frequency variants with a large effect on AOM. We discovered that women homozygous for the stop-gain variant rs117316434 (A) in CCDC201 (p.(Arg162Ter), minor allele frequency ~1%) reached menopause 9 years earlier than other women (P = 1.3 × 10−15). The genotype is present in one in 10,000 northern European women and leads to primary ovarian insufficiency in close to half of them. Consequently, homozygotes have fewer children, and the age at last childbirth is 5 years earlier (P = 3.8 × 10−5). The CCDC201 gene was only found in humans in 2022 and is highly expressed in oocytes. Homozygosity for CCDC201 loss-of-function has a substantial impact on female reproductive health, and homozygotes would benefit from reproductive counseling and treatment for symptoms of early menopause. Genome-wide analysis of age at menopause under a recessive model identifies a stop-gain variant in CCDC201 associated with primary ovarian insufficiency. This homozygous genotype is present in 1 in 10,000 women of northern European ancestry.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 9","pages":"1804-1810"},"PeriodicalIF":31.7,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01885-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142081006","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 : 2024-08-27DOI: 10.1038/s41588-024-01884-7
Oliver S. Burren, Ryan S. Dhindsa, Sri V. V. Deevi, Sean Wen, Abhishek Nag, Jonathan Mitchell, Fengyuan Hu, Douglas P. Loesch, Katherine R. Smith, Neetu Razdan, Henric Olsson, Adam Platt, Dimitrios Vitsios, Qiang Wu, AstraZeneca Genomics Initiative, Veryan Codd, Christopher P. Nelson, Nilesh J. Samani, Ruth E. March, Sebastian Wasilewski, Keren Carss, Margarete Fabre, Quanli Wang, Menelas N. Pangalos, Slavé Petrovski
Telomeres protect chromosome ends from damage and their length is linked with human disease and aging. We developed a joint telomere length metric, combining quantitative PCR and whole-genome sequencing measurements from 462,666 UK Biobank participants. This metric increased SNP heritability, suggesting that it better captures genetic regulation of telomere length. Exome-wide rare-variant and gene-level collapsing association studies identified 64 variants and 30 genes significantly associated with telomere length, including allelic series in ACD and RTEL1. Notably, 16% of these genes are known drivers of clonal hematopoiesis—an age-related somatic mosaicism associated with myeloid cancers and several nonmalignant diseases. Somatic variant analyses revealed gene-specific associations with telomere length, including lengthened telomeres in individuals with large SRSF2-mutant clones, compared with shortened telomeres in individuals with clonal expansions driven by other genes. Collectively, our findings demonstrate the impact of rare variants on telomere length, with larger effects observed among genes also associated with clonal hematopoiesis. Genome-wide association analysis of an improved telomere length score, calculated from quantitative PCR and whole-genome sequencing measurements in 462,666 individuals in the UK Biobank, identifies novel genes and variants underlying this trait.
{"title":"Genetic architecture of telomere length in 462,666 UK Biobank whole-genome sequences","authors":"Oliver S. Burren, Ryan S. Dhindsa, Sri V. V. Deevi, Sean Wen, Abhishek Nag, Jonathan Mitchell, Fengyuan Hu, Douglas P. Loesch, Katherine R. Smith, Neetu Razdan, Henric Olsson, Adam Platt, Dimitrios Vitsios, Qiang Wu, AstraZeneca Genomics Initiative, Veryan Codd, Christopher P. Nelson, Nilesh J. Samani, Ruth E. March, Sebastian Wasilewski, Keren Carss, Margarete Fabre, Quanli Wang, Menelas N. Pangalos, Slavé Petrovski","doi":"10.1038/s41588-024-01884-7","DOIUrl":"10.1038/s41588-024-01884-7","url":null,"abstract":"Telomeres protect chromosome ends from damage and their length is linked with human disease and aging. We developed a joint telomere length metric, combining quantitative PCR and whole-genome sequencing measurements from 462,666 UK Biobank participants. This metric increased SNP heritability, suggesting that it better captures genetic regulation of telomere length. Exome-wide rare-variant and gene-level collapsing association studies identified 64 variants and 30 genes significantly associated with telomere length, including allelic series in ACD and RTEL1. Notably, 16% of these genes are known drivers of clonal hematopoiesis—an age-related somatic mosaicism associated with myeloid cancers and several nonmalignant diseases. Somatic variant analyses revealed gene-specific associations with telomere length, including lengthened telomeres in individuals with large SRSF2-mutant clones, compared with shortened telomeres in individuals with clonal expansions driven by other genes. Collectively, our findings demonstrate the impact of rare variants on telomere length, with larger effects observed among genes also associated with clonal hematopoiesis. Genome-wide association analysis of an improved telomere length score, calculated from quantitative PCR and whole-genome sequencing measurements in 462,666 individuals in the UK Biobank, identifies novel genes and variants underlying this trait.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 9","pages":"1832-1840"},"PeriodicalIF":31.7,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01884-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142081005","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}
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