Pub Date : 2024-09-23DOI: 10.1038/s41588-024-01910-8
V. Kartik Chundru, Zhancheng Zhang, Klaudia Walter, Sarah J. Lindsay, Petr Danecek, Ruth Y. Eberhardt, Eugene J. Gardner, Daniel S. Malawsky, Emilie M. Wigdor, Rebecca Torene, Kyle Retterer, Caroline F. Wright, Hildur Ólafsdóttir, Maria J. Guillen Sacoto, Akif Ayaz, Ismail Hakki Akbeyaz, Dilşad Türkdoğan, Aaisha Ibrahim Al Balushi, Aida Bertoli-Avella, Peter Bauer, Emmanuelle Szenker-Ravi, Bruno Reversade, Kirsty McWalter, Eamonn Sheridan, Helen V. Firth, Matthew E. Hurles, Kaitlin E. Samocha, Vincent D. Ustach, Hilary C. Martin
Autosomal recessive coding variants are well-known causes of rare disorders. We quantified the contribution of these variants to developmental disorders in a large, ancestrally diverse cohort comprising 29,745 trios, of whom 20.4% had genetically inferred non-European ancestries. The estimated fraction of patients attributable to exome-wide autosomal recessive coding variants ranged from ~2–19% across genetically inferred ancestry groups and was significantly correlated with average autozygosity. Established autosomal recessive developmental disorder-associated (ARDD) genes explained 84.0% of the total autosomal recessive coding burden, and 34.4% of the burden in these established genes was explained by variants not already reported as pathogenic in ClinVar. Statistical analyses identified two novel ARDD genes: KBTBD2 and ZDHHC16. This study expands our understanding of the genetic architecture of developmental disorders across diverse genetically inferred ancestry groups and suggests that improving strategies for interpreting missense variants in known ARDD genes may help diagnose more patients than discovering the remaining genes. Analysis of autosomal recessive coding variants in 29,745 trios from the DDD study and GeneDx provides insights into the genetic architecture of developmental disorders across ancestrally diverse populations.
{"title":"Federated analysis of autosomal recessive coding variants in 29,745 developmental disorder patients from diverse populations","authors":"V. Kartik Chundru, Zhancheng Zhang, Klaudia Walter, Sarah J. Lindsay, Petr Danecek, Ruth Y. Eberhardt, Eugene J. Gardner, Daniel S. Malawsky, Emilie M. Wigdor, Rebecca Torene, Kyle Retterer, Caroline F. Wright, Hildur Ólafsdóttir, Maria J. Guillen Sacoto, Akif Ayaz, Ismail Hakki Akbeyaz, Dilşad Türkdoğan, Aaisha Ibrahim Al Balushi, Aida Bertoli-Avella, Peter Bauer, Emmanuelle Szenker-Ravi, Bruno Reversade, Kirsty McWalter, Eamonn Sheridan, Helen V. Firth, Matthew E. Hurles, Kaitlin E. Samocha, Vincent D. Ustach, Hilary C. Martin","doi":"10.1038/s41588-024-01910-8","DOIUrl":"10.1038/s41588-024-01910-8","url":null,"abstract":"Autosomal recessive coding variants are well-known causes of rare disorders. We quantified the contribution of these variants to developmental disorders in a large, ancestrally diverse cohort comprising 29,745 trios, of whom 20.4% had genetically inferred non-European ancestries. The estimated fraction of patients attributable to exome-wide autosomal recessive coding variants ranged from ~2–19% across genetically inferred ancestry groups and was significantly correlated with average autozygosity. Established autosomal recessive developmental disorder-associated (ARDD) genes explained 84.0% of the total autosomal recessive coding burden, and 34.4% of the burden in these established genes was explained by variants not already reported as pathogenic in ClinVar. Statistical analyses identified two novel ARDD genes: KBTBD2 and ZDHHC16. This study expands our understanding of the genetic architecture of developmental disorders across diverse genetically inferred ancestry groups and suggests that improving strategies for interpreting missense variants in known ARDD genes may help diagnose more patients than discovering the remaining genes. Analysis of autosomal recessive coding variants in 29,745 trios from the DDD study and GeneDx provides insights into the genetic architecture of developmental disorders across ancestrally diverse populations.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":null,"pages":null},"PeriodicalIF":31.7,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01910-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142276880","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 : 2024-09-23DOI: 10.1038/s41588-024-01875-8
Albert Herms, David Fernandez-Antoran, Maria P. Alcolea, Argyro Kalogeropoulou, Ujjwal Banerjee, Gabriel Piedrafita, Emilie Abby, Jose Antonio Valverde-Lopez, Inês S. Ferreira, Irene Caseda, Maria T. Bejar, Stefan C. Dentro, Sara Vidal-Notari, Swee Hoe Ong, Bartomeu Colom, Kasumi Murai, Charlotte King, Krishnaa Mahbubani, Kourosh Saeb-Parsy, Alan R. Lowe, Moritz Gerstung, Philip H. Jones
Aging epithelia are colonized by somatic mutations, which are subjected to selection influenced by intrinsic and extrinsic factors. The lack of suitable culture systems has slowed the study of this and other long-term biological processes. Here, we describe epithelioids, a facile, cost-effective method of culturing multiple mouse and human epithelia. Esophageal epithelioids self-maintain without passaging for at least 1 year, maintaining a three-dimensional structure with proliferative basal cells that differentiate into suprabasal cells, which eventually shed and retain genomic stability. Live imaging over 5 months showed that epithelioids replicate in vivo cell dynamics. Epithelioids support genetic manipulation and enable the study of mutant cell competition and selection in three-dimensional epithelia, and show how anti-cancer treatments modulate competition between transformed and wild-type cells. Finally, a targeted CRISPR–Cas9 screen shows that epithelioids recapitulate mutant gene selection in aging human esophagus and identifies additional drivers of clonal expansion, resolving the genetic networks underpinning competitive fitness. Epithelioids are genetically stable, self-sustaining three-dimensional cultures. They may be used to investigate various aspects of epithelial biology over several months without need for passaging. In this paper, mouse epithelioids are used to identify drivers of clonal expansion in the esophagus.
{"title":"Self-sustaining long-term 3D epithelioid cultures reveal drivers of clonal expansion in esophageal epithelium","authors":"Albert Herms, David Fernandez-Antoran, Maria P. Alcolea, Argyro Kalogeropoulou, Ujjwal Banerjee, Gabriel Piedrafita, Emilie Abby, Jose Antonio Valverde-Lopez, Inês S. Ferreira, Irene Caseda, Maria T. Bejar, Stefan C. Dentro, Sara Vidal-Notari, Swee Hoe Ong, Bartomeu Colom, Kasumi Murai, Charlotte King, Krishnaa Mahbubani, Kourosh Saeb-Parsy, Alan R. Lowe, Moritz Gerstung, Philip H. Jones","doi":"10.1038/s41588-024-01875-8","DOIUrl":"10.1038/s41588-024-01875-8","url":null,"abstract":"Aging epithelia are colonized by somatic mutations, which are subjected to selection influenced by intrinsic and extrinsic factors. The lack of suitable culture systems has slowed the study of this and other long-term biological processes. Here, we describe epithelioids, a facile, cost-effective method of culturing multiple mouse and human epithelia. Esophageal epithelioids self-maintain without passaging for at least 1 year, maintaining a three-dimensional structure with proliferative basal cells that differentiate into suprabasal cells, which eventually shed and retain genomic stability. Live imaging over 5 months showed that epithelioids replicate in vivo cell dynamics. Epithelioids support genetic manipulation and enable the study of mutant cell competition and selection in three-dimensional epithelia, and show how anti-cancer treatments modulate competition between transformed and wild-type cells. Finally, a targeted CRISPR–Cas9 screen shows that epithelioids recapitulate mutant gene selection in aging human esophagus and identifies additional drivers of clonal expansion, resolving the genetic networks underpinning competitive fitness. Epithelioids are genetically stable, self-sustaining three-dimensional cultures. They may be used to investigate various aspects of epithelial biology over several months without need for passaging. In this paper, mouse epithelioids are used to identify drivers of clonal expansion in the esophagus.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":null,"pages":null},"PeriodicalIF":31.7,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01875-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142276877","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 : 2024-09-23DOI: 10.1038/s41588-024-01917-1
Bharati Jadhav, Paras Garg, Joke J. F. A. van Vugt, Kristina Ibanez, Delia Gagliardi, William Lee, Mariya Shadrina, Tom Mokveld, Egor Dolzhenko, Alejandro Martin-Trujillo, Scott J. Gies, Gabrielle Altman, Clarissa Rocca, Mafalda Barbosa, Miten Jain, Nayana Lahiri, Katherine Lachlan, Henry Houlden, Benedict Paten, Genomics England Research Consortium, Project MinE ALS Sequencing Consortium, Jan Veldink, Arianna Tucci, Andrew J. Sharp
GC-rich tandem repeat expansions (TREs) are often associated with DNA methylation, gene silencing and folate-sensitive fragile sites, and underlie several congenital and late-onset disorders. Through a combination of DNA-methylation profiling and tandem repeat genotyping, we identified 24 methylated TREs and investigated their effects on human traits using phenome-wide association studies in 168,641 individuals from the UK Biobank, identifying 156 significant TRE–trait associations involving 17 different TREs. Of these, a GCC expansion in the promoter of AFF3 was associated with a 2.4-fold reduced probability of completing secondary education, an effect size comparable to several recurrent pathogenic microdeletions. In a cohort of 6,371 probands with neurodevelopmental problems of suspected genetic etiology, we observed a significant enrichment of AFF3 expansions compared with controls. With a population prevalence that is at least fivefold higher than the TRE that causes fragile X syndrome, AFF3 expansions represent a major cause of neurodevelopmental delay. Phenome-wide analysis in the UK Biobank identifies GC-rich tandem repeat expansions associated with a range of traits, including a GCC expansion in AFF3 contributing to intellectual disability.
{"title":"A phenome-wide association study of methylated GC-rich repeats identifies a GCC repeat expansion in AFF3 associated with intellectual disability","authors":"Bharati Jadhav, Paras Garg, Joke J. F. A. van Vugt, Kristina Ibanez, Delia Gagliardi, William Lee, Mariya Shadrina, Tom Mokveld, Egor Dolzhenko, Alejandro Martin-Trujillo, Scott J. Gies, Gabrielle Altman, Clarissa Rocca, Mafalda Barbosa, Miten Jain, Nayana Lahiri, Katherine Lachlan, Henry Houlden, Benedict Paten, Genomics England Research Consortium, Project MinE ALS Sequencing Consortium, Jan Veldink, Arianna Tucci, Andrew J. Sharp","doi":"10.1038/s41588-024-01917-1","DOIUrl":"10.1038/s41588-024-01917-1","url":null,"abstract":"GC-rich tandem repeat expansions (TREs) are often associated with DNA methylation, gene silencing and folate-sensitive fragile sites, and underlie several congenital and late-onset disorders. Through a combination of DNA-methylation profiling and tandem repeat genotyping, we identified 24 methylated TREs and investigated their effects on human traits using phenome-wide association studies in 168,641 individuals from the UK Biobank, identifying 156 significant TRE–trait associations involving 17 different TREs. Of these, a GCC expansion in the promoter of AFF3 was associated with a 2.4-fold reduced probability of completing secondary education, an effect size comparable to several recurrent pathogenic microdeletions. In a cohort of 6,371 probands with neurodevelopmental problems of suspected genetic etiology, we observed a significant enrichment of AFF3 expansions compared with controls. With a population prevalence that is at least fivefold higher than the TRE that causes fragile X syndrome, AFF3 expansions represent a major cause of neurodevelopmental delay. Phenome-wide analysis in the UK Biobank identifies GC-rich tandem repeat expansions associated with a range of traits, including a GCC expansion in AFF3 contributing to intellectual disability.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":null,"pages":null},"PeriodicalIF":31.7,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142276876","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 : 2024-09-18DOI: 10.1038/s41588-024-01912-6
Blockade of primary genomic binding sites with small molecules causes redistribution of the transcription factor PU.1 to alternative binding sites; its transcriptional activity at these sites activates secondary gene networks that drive myeloid cell differentiation.
{"title":"Chemical restriction of PU.1 genomic binding sites activates alternate gene networks","authors":"","doi":"10.1038/s41588-024-01912-6","DOIUrl":"10.1038/s41588-024-01912-6","url":null,"abstract":"Blockade of primary genomic binding sites with small molecules causes redistribution of the transcription factor PU.1 to alternative binding sites; its transcriptional activity at these sites activates secondary gene networks that drive myeloid cell differentiation.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":null,"pages":null},"PeriodicalIF":31.7,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236233","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 : 2024-09-18DOI: 10.1038/s41588-024-01914-4
Ateeq M. Khaliq, Meenakshi Rajamohan, Omer Saeed, Kimia Mansouri, Asif Adil, Chi Zhang, Anita Turk, Julienne L. Carstens, Michael House, Sikander Hayat, Ganji P. Nagaraju, Sam G. Pappas, Y. Alan. Wang, Nicholas J. Zyromski, Mateusz Opyrchal, Kelvin P. Lee, Heather O’Hagan, Bassel El Rayes, Ashiq Masood
Although the spatial, cellular and molecular landscapes of resected pancreatic ductal adenocarcinoma (PDAC) are well documented, the characteristics of its metastatic ecology remain elusive. By applying spatially resolved transcriptomics to matched primary and metastatic PDAC samples, we discovered a conserved continuum of fibrotic, metabolic and immunosuppressive spatial ecotypes across anatomical regions. We observed spatial tumor microenvironment heterogeneity spanning beyond that previously appreciated in PDAC. Through comparative analysis, we show that the spatial ecotypes exhibit distinct enrichment between primary and metastatic sites, implying adaptability to the local environment for survival and progression. The invasive border ecotype exhibits both pro-tumorigenic and anti-tumorigenic cell-type enrichment, suggesting a potential immunotherapy target. The ecotype heterogeneity across patients emphasizes the need to map individual patient landscapes to develop personalized treatment strategies. Collectively, our findings provide critical insights into metastatic PDAC biology and serve as a valuable resource for future therapeutic exploration and molecular investigations. Spot-based spatial transcriptomic analysis of paired primary and metastatic pancreatic cancers identifies cellular, metabolic and fibrotic changes in ecotypes associated with progression, highlighting the contribution of the tumor microenvironment.
{"title":"Spatial transcriptomic analysis of primary and metastatic pancreatic cancers highlights tumor microenvironmental heterogeneity","authors":"Ateeq M. Khaliq, Meenakshi Rajamohan, Omer Saeed, Kimia Mansouri, Asif Adil, Chi Zhang, Anita Turk, Julienne L. Carstens, Michael House, Sikander Hayat, Ganji P. Nagaraju, Sam G. Pappas, Y. Alan. Wang, Nicholas J. Zyromski, Mateusz Opyrchal, Kelvin P. Lee, Heather O’Hagan, Bassel El Rayes, Ashiq Masood","doi":"10.1038/s41588-024-01914-4","DOIUrl":"10.1038/s41588-024-01914-4","url":null,"abstract":"Although the spatial, cellular and molecular landscapes of resected pancreatic ductal adenocarcinoma (PDAC) are well documented, the characteristics of its metastatic ecology remain elusive. By applying spatially resolved transcriptomics to matched primary and metastatic PDAC samples, we discovered a conserved continuum of fibrotic, metabolic and immunosuppressive spatial ecotypes across anatomical regions. We observed spatial tumor microenvironment heterogeneity spanning beyond that previously appreciated in PDAC. Through comparative analysis, we show that the spatial ecotypes exhibit distinct enrichment between primary and metastatic sites, implying adaptability to the local environment for survival and progression. The invasive border ecotype exhibits both pro-tumorigenic and anti-tumorigenic cell-type enrichment, suggesting a potential immunotherapy target. The ecotype heterogeneity across patients emphasizes the need to map individual patient landscapes to develop personalized treatment strategies. Collectively, our findings provide critical insights into metastatic PDAC biology and serve as a valuable resource for future therapeutic exploration and molecular investigations. Spot-based spatial transcriptomic analysis of paired primary and metastatic pancreatic cancers identifies cellular, metabolic and fibrotic changes in ecotypes associated with progression, highlighting the contribution of the tumor microenvironment.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":null,"pages":null},"PeriodicalIF":31.7,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236672","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 : 2024-09-18DOI: 10.1038/s41588-024-01908-2
Eleni Friligkou, Solveig Løkhammer, Brenda Cabrera-Mendoza, Jie Shen, Jun He, Giovanni Deiana, Mihaela Diana Zanoaga, Zeynep Asgel, Abigail Pilcher, Luciana Di Lascio, Ana Makharashvili, Dora Koller, Daniel S. Tylee, Gita A. Pathak, Renato Polimanti
We leveraged information from more than 1.2 million participants, including 97,383 cases, to investigate the genetics of anxiety disorders across five continental groups. Through ancestry-specific and cross-ancestry genome-wide association studies, we identified 51 anxiety-associated loci, 39 of which were novel. In addition, polygenic risk scores derived from individuals of European descent were associated with anxiety in African, admixed American and East Asian groups. The heritability of anxiety was enriched for genes expressed in the limbic system, cerebral cortex, cerebellum, metencephalon, entorhinal cortex and brain stem. Transcriptome-wide and proteome-wide analyses highlighted 115 genes associated with anxiety through brain-specific and cross-tissue regulation. Anxiety also showed global and local genetic correlations with depression, schizophrenia and bipolar disorder and widespread pleiotropy with several physical health domains. Overall, this study expands our knowledge regarding the genetic risk and pathogenesis of anxiety disorders, highlighting the importance of investigating diverse populations and integrating multi-omics information. A large-scale multi-ancestry genome-wide association study of European, African, admixed American, South Asian and East Asian ancestries provides insights into the pathogenesis of anxiety disorders.
{"title":"Gene discovery and biological insights into anxiety disorders from a large-scale multi-ancestry genome-wide association study","authors":"Eleni Friligkou, Solveig Løkhammer, Brenda Cabrera-Mendoza, Jie Shen, Jun He, Giovanni Deiana, Mihaela Diana Zanoaga, Zeynep Asgel, Abigail Pilcher, Luciana Di Lascio, Ana Makharashvili, Dora Koller, Daniel S. Tylee, Gita A. Pathak, Renato Polimanti","doi":"10.1038/s41588-024-01908-2","DOIUrl":"10.1038/s41588-024-01908-2","url":null,"abstract":"We leveraged information from more than 1.2 million participants, including 97,383 cases, to investigate the genetics of anxiety disorders across five continental groups. Through ancestry-specific and cross-ancestry genome-wide association studies, we identified 51 anxiety-associated loci, 39 of which were novel. In addition, polygenic risk scores derived from individuals of European descent were associated with anxiety in African, admixed American and East Asian groups. The heritability of anxiety was enriched for genes expressed in the limbic system, cerebral cortex, cerebellum, metencephalon, entorhinal cortex and brain stem. Transcriptome-wide and proteome-wide analyses highlighted 115 genes associated with anxiety through brain-specific and cross-tissue regulation. Anxiety also showed global and local genetic correlations with depression, schizophrenia and bipolar disorder and widespread pleiotropy with several physical health domains. Overall, this study expands our knowledge regarding the genetic risk and pathogenesis of anxiety disorders, highlighting the importance of investigating diverse populations and integrating multi-omics information. A large-scale multi-ancestry genome-wide association study of European, African, admixed American, South Asian and East Asian ancestries provides insights into the pathogenesis of anxiety disorders.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":null,"pages":null},"PeriodicalIF":31.7,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236234","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 : 2024-09-18DOI: 10.1038/s41588-024-01911-7
Samuel J. Taylor, Jacob Stauber, Oliver Bohorquez, Goichi Tatsumi, Rajni Kumari, Joyeeta Chakraborty, Boris A. Bartholdy, Emily Schwenger, Sriram Sundaravel, Abdelbasset A. Farahat, Justin C. Wheat, Mendel Goldfinger, Amit Verma, Arvind Kumar, David W. Boykin, Kristy R. Stengel, Gregory M. K. Poon, Ulrich Steidl
Transcription factor (TF) DNA-binding dynamics govern cell fate and identity. However, our ability to pharmacologically control TF localization is limited. Here we leverage chemically driven binding site restriction leading to robust and DNA-sequence-specific redistribution of PU.1, a pioneer TF pertinent to many hematopoietic malignancies. Through an innovative technique, ‘CLICK-on-CUT&Tag’, we characterize the hierarchy of de novo PU.1 motifs, predicting occupancy in the PU.1 cistrome under binding site restriction. Temporal and single-molecule studies of binding site restriction uncover the pioneering dynamics of native PU.1 and identify the paradoxical activation of an alternate target gene set driven by PU.1 localization to second-tier binding sites. These transcriptional changes were corroborated by genetic blockade and site-specific reporter assays. Binding site restriction and subsequent PU.1 network rewiring causes primary human leukemia cells to differentiate. In summary, pharmacologically induced TF redistribution can be harnessed to govern TF localization, actuate alternate gene networks and direct cell fate. Chemically driven blockade of PU.1 binding sites leads to its genome-wide redistribution. PU.1 network rewiring causes human acute myeloid leukemia cells to differentiate.
转录因子（TF）的 DNA 结合动力学决定着细胞的命运和特性。然而，我们通过药物控制转录因子定位的能力有限。在这里，我们利用化学驱动的结合位点限制，实现了与许多造血恶性肿瘤相关的先驱转录因子 PU.1 的稳健且具有 DNA 序列特异性的重新分布。通过一种创新技术 "CLICK-on-CUT&Tag"，我们描述了PU.1新图案的层次结构，预测了在结合位点限制下PU.1词簇中的占位情况。对结合位点限制的时间和单分子研究揭示了原生 PU.1 的先驱动态，并确定了 PU.1 定位于二级结合位点所驱动的另一个目标基因集的矛盾激活。基因阻断和位点特异性报告实验证实了这些转录变化。结合位点限制和随后的 PU.1 网络重新布线导致原代人类白血病细胞分化。总之，可以利用药理诱导的 TF 重新分布来控制 TF 定位、激活交替基因网络并指导细胞命运。
{"title":"Pharmacological restriction of genomic binding sites redirects PU.1 pioneer transcription factor activity","authors":"Samuel J. Taylor, Jacob Stauber, Oliver Bohorquez, Goichi Tatsumi, Rajni Kumari, Joyeeta Chakraborty, Boris A. Bartholdy, Emily Schwenger, Sriram Sundaravel, Abdelbasset A. Farahat, Justin C. Wheat, Mendel Goldfinger, Amit Verma, Arvind Kumar, David W. Boykin, Kristy R. Stengel, Gregory M. K. Poon, Ulrich Steidl","doi":"10.1038/s41588-024-01911-7","DOIUrl":"10.1038/s41588-024-01911-7","url":null,"abstract":"Transcription factor (TF) DNA-binding dynamics govern cell fate and identity. However, our ability to pharmacologically control TF localization is limited. Here we leverage chemically driven binding site restriction leading to robust and DNA-sequence-specific redistribution of PU.1, a pioneer TF pertinent to many hematopoietic malignancies. Through an innovative technique, ‘CLICK-on-CUT&Tag’, we characterize the hierarchy of de novo PU.1 motifs, predicting occupancy in the PU.1 cistrome under binding site restriction. Temporal and single-molecule studies of binding site restriction uncover the pioneering dynamics of native PU.1 and identify the paradoxical activation of an alternate target gene set driven by PU.1 localization to second-tier binding sites. These transcriptional changes were corroborated by genetic blockade and site-specific reporter assays. Binding site restriction and subsequent PU.1 network rewiring causes primary human leukemia cells to differentiate. In summary, pharmacologically induced TF redistribution can be harnessed to govern TF localization, actuate alternate gene networks and direct cell fate. Chemically driven blockade of PU.1 binding sites leads to its genome-wide redistribution. PU.1 network rewiring causes human acute myeloid leukemia cells to differentiate.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":null,"pages":null},"PeriodicalIF":31.7,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01911-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236691","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 : 2024-09-17DOI: 10.1038/s41588-024-01905-5
Abdulkadir Abakir, Alexey Ruzov
R-loops contain DNA:RNA hybrids and an unpaired single-stranded DNA. N6-methyladenosine (m6A) has been reported to modulate R-loop levels, but with varying outcomes (R-loop resolution versus stabilization). We propose that in different contexts, m6A may either directly prevent R-loop accumulation or stabilize R-loops via the formation of RNA abasic sites.
R 环包含 DNA:RNA 杂交体和未配对的单链 DNA。据报道，N6-甲基腺苷（m6A）可调节 R 环水平，但结果各不相同（R 环解析与稳定）。我们认为，在不同的情况下，m6A 可直接阻止 R 环的积累，或通过形成 RNA 终止位点来稳定 R 环。
{"title":"A model for a dual function of N6-methyladenosine in R-loop regulation","authors":"Abdulkadir Abakir, Alexey Ruzov","doi":"10.1038/s41588-024-01905-5","DOIUrl":"10.1038/s41588-024-01905-5","url":null,"abstract":"R-loops contain DNA:RNA hybrids and an unpaired single-stranded DNA. N6-methyladenosine (m6A) has been reported to modulate R-loop levels, but with varying outcomes (R-loop resolution versus stabilization). We propose that in different contexts, m6A may either directly prevent R-loop accumulation or stabilize R-loops via the formation of RNA abasic sites.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":null,"pages":null},"PeriodicalIF":31.7,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142235125","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 : 2024-09-16DOI: 10.1038/s41588-024-01900-w
Philip J. Law, James Studd, James Smith, Jayaram Vijayakrishnan, Bradley T. Harris, Maria Mandelia, Charlie Mills, Malcolm G. Dunlop, Richard S. Houlston
Genome-wide association studies of colorectal cancer (CRC) have identified 170 autosomal risk loci. However, for most of these, the functional variants and their target genes are unknown. Here, we perform statistical fine-mapping incorporating tissue-specific epigenetic annotations and massively parallel reporter assays to systematically prioritize functional variants for each CRC risk locus. We identify plausible causal variants for the 170 risk loci, with a single variant for 40. We link these variants to 208 target genes by analyzing colon-specific quantitative trait loci and implementing the activity-by-contact model, which integrates epigenomic features and Micro-C data, to predict enhancer–gene connections. By deciphering CRC risk loci, we identify direct links between risk variants and target genes, providing further insight into the molecular basis of CRC susceptibility and highlighting potential pharmaceutical targets for prevention and treatment. This study uses a combination of in silico and experimental techniques to ascribe target genes to 170 risk loci for colorectal cancer.
{"title":"Systematic prioritization of functional variants and effector genes underlying colorectal cancer risk","authors":"Philip J. Law, James Studd, James Smith, Jayaram Vijayakrishnan, Bradley T. Harris, Maria Mandelia, Charlie Mills, Malcolm G. Dunlop, Richard S. Houlston","doi":"10.1038/s41588-024-01900-w","DOIUrl":"10.1038/s41588-024-01900-w","url":null,"abstract":"Genome-wide association studies of colorectal cancer (CRC) have identified 170 autosomal risk loci. However, for most of these, the functional variants and their target genes are unknown. Here, we perform statistical fine-mapping incorporating tissue-specific epigenetic annotations and massively parallel reporter assays to systematically prioritize functional variants for each CRC risk locus. We identify plausible causal variants for the 170 risk loci, with a single variant for 40. We link these variants to 208 target genes by analyzing colon-specific quantitative trait loci and implementing the activity-by-contact model, which integrates epigenomic features and Micro-C data, to predict enhancer–gene connections. By deciphering CRC risk loci, we identify direct links between risk variants and target genes, providing further insight into the molecular basis of CRC susceptibility and highlighting potential pharmaceutical targets for prevention and treatment. This study uses a combination of in silico and experimental techniques to ascribe target genes to 170 risk loci for colorectal cancer.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":null,"pages":null},"PeriodicalIF":31.7,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01900-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142234445","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 : 2024-09-16DOI: 10.1038/s41588-024-01923-3
Shushan Toneyan, Peter K. Koo
The rise of large-scale, sequence-based deep neural networks (DNNs) for predicting gene expression has introduced challenges in their evaluation and interpretation. Current evaluations align DNN predictions with orthogonal experimental data, providing insights into generalization but offering limited insights into their decision-making process. Existing model explainability tools focus mainly on motif analysis, which becomes complex when interpreting longer sequences. Here we present cis-regulatory element model explanations (CREME), an in silico perturbation toolkit that interprets the rules of gene regulation learned by a genomic DNN. Applying CREME to Enformer, a state-of-the-art DNN, we identify cis-regulatory elements that enhance or silence gene expression and characterize their complex interactions. CREME can provide interpretations across multiple scales of genomic organization, from cis-regulatory elements to fine-mapped functional sequence elements within them, offering high-resolution insights into the regulatory architecture of the genome. CREME provides a powerful toolkit for translating the predictions of genomic DNNs into mechanistic insights of gene regulation. CREME is an extensible computational tool for investigating cis-regulation via in silico perturbations of neural network-based DNA sequence models such as Enformer, identifying complex interactions between a gene’s regulatory elements.
{"title":"Interpreting cis-regulatory interactions from large-scale deep neural networks","authors":"Shushan Toneyan, Peter K. Koo","doi":"10.1038/s41588-024-01923-3","DOIUrl":"10.1038/s41588-024-01923-3","url":null,"abstract":"The rise of large-scale, sequence-based deep neural networks (DNNs) for predicting gene expression has introduced challenges in their evaluation and interpretation. Current evaluations align DNN predictions with orthogonal experimental data, providing insights into generalization but offering limited insights into their decision-making process. Existing model explainability tools focus mainly on motif analysis, which becomes complex when interpreting longer sequences. Here we present cis-regulatory element model explanations (CREME), an in silico perturbation toolkit that interprets the rules of gene regulation learned by a genomic DNN. Applying CREME to Enformer, a state-of-the-art DNN, we identify cis-regulatory elements that enhance or silence gene expression and characterize their complex interactions. CREME can provide interpretations across multiple scales of genomic organization, from cis-regulatory elements to fine-mapped functional sequence elements within them, offering high-resolution insights into the regulatory architecture of the genome. CREME provides a powerful toolkit for translating the predictions of genomic DNNs into mechanistic insights of gene regulation. CREME is an extensible computational tool for investigating cis-regulation via in silico perturbations of neural network-based DNA sequence models such as Enformer, identifying complex interactions between a gene’s regulatory elements.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":null,"pages":null},"PeriodicalIF":31.7,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142234509","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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