Pub Date : 2025-01-22DOI: 10.1038/s41588-024-02054-5
Ricardo Mouro Pinto, Ryan Murtha, António Azevedo, Cameron Douglas, Marina Kovalenko, Jessica Ulloa, Steven Crescenti, Zoe Burch, Esaria Oliver, Maheswaran Kesavan, Shota Shibata, Antonia Vitalo, Eduarda Mota-Silva, Marion J. Riggs, Kevin Correia, Emanuela Elezi, Brigitte Demelo, Jeffrey B. Carroll, Tammy Gillis, James F. Gusella, Marcy E. MacDonald, Vanessa C. Wheeler
Huntington’s disease, one of more than 50 inherited repeat expansion disorders1, is a dominantly inherited neurodegenerative disease caused by a CAG expansion in HTT2. Inherited CAG repeat length is the primary determinant of age of onset, with human genetic studies underscoring that the disease is driven by the CAG length-dependent propensity of the repeat to further expand in the brain3–9. Routes to slowing somatic CAG expansion, therefore, hold promise for disease-modifying therapies. Several DNA repair genes, notably in the mismatch repair pathway, modify somatic expansion in Huntington’s disease mouse models10. To identify novel modifiers of somatic expansion, we used CRISPR–Cas9 editing in Huntington’s disease knock-in mice to enable in vivo screening of expansion-modifier candidates at scale. This included testing of Huntington’s disease onset modifier genes emerging from human genome-wide association studies as well as interactions between modifier genes, providing insight into pathways underlying CAG expansion and potential therapeutic targets. A novel in vivo screening strategy identifies new modifiers of somatic CAG repeat expansion that contribute to age of onset in Huntington’s disease.
{"title":"In vivo CRISPR–Cas9 genome editing in mice identifies genetic modifiers of somatic CAG repeat instability in Huntington’s disease","authors":"Ricardo Mouro Pinto, Ryan Murtha, António Azevedo, Cameron Douglas, Marina Kovalenko, Jessica Ulloa, Steven Crescenti, Zoe Burch, Esaria Oliver, Maheswaran Kesavan, Shota Shibata, Antonia Vitalo, Eduarda Mota-Silva, Marion J. Riggs, Kevin Correia, Emanuela Elezi, Brigitte Demelo, Jeffrey B. Carroll, Tammy Gillis, James F. Gusella, Marcy E. MacDonald, Vanessa C. Wheeler","doi":"10.1038/s41588-024-02054-5","DOIUrl":"10.1038/s41588-024-02054-5","url":null,"abstract":"Huntington’s disease, one of more than 50 inherited repeat expansion disorders1, is a dominantly inherited neurodegenerative disease caused by a CAG expansion in HTT2. Inherited CAG repeat length is the primary determinant of age of onset, with human genetic studies underscoring that the disease is driven by the CAG length-dependent propensity of the repeat to further expand in the brain3–9. Routes to slowing somatic CAG expansion, therefore, hold promise for disease-modifying therapies. Several DNA repair genes, notably in the mismatch repair pathway, modify somatic expansion in Huntington’s disease mouse models10. To identify novel modifiers of somatic expansion, we used CRISPR–Cas9 editing in Huntington’s disease knock-in mice to enable in vivo screening of expansion-modifier candidates at scale. This included testing of Huntington’s disease onset modifier genes emerging from human genome-wide association studies as well as interactions between modifier genes, providing insight into pathways underlying CAG expansion and potential therapeutic targets. A novel in vivo screening strategy identifies new modifiers of somatic CAG repeat expansion that contribute to age of onset in Huntington’s disease.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 2","pages":"314-322"},"PeriodicalIF":31.7,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-02054-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142992382","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 : 2025-01-22DOI: 10.1038/s41588-024-02055-4
Suphinya Sathitloetsakun, Myriam Heiman
A novel in vivo CRISPR screening platform identifies genetic modifiers of huntingtin CAG repeat somatic instability. These modifiers include known and novel genes that are promising therapeutic targets for Huntington’s disease.
{"title":"Defining genes and pathways that modify huntingtin CAG repeat somatic instability in vivo","authors":"Suphinya Sathitloetsakun, Myriam Heiman","doi":"10.1038/s41588-024-02055-4","DOIUrl":"10.1038/s41588-024-02055-4","url":null,"abstract":"A novel in vivo CRISPR screening platform identifies genetic modifiers of huntingtin CAG repeat somatic instability. These modifiers include known and novel genes that are promising therapeutic targets for Huntington’s disease.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 2","pages":"281-282"},"PeriodicalIF":31.7,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142991913","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 : 2025-01-20DOI: 10.1038/s41588-025-02090-9
Samson H. Fong, Brent M. Kuenzi, Nicole M. Mattson, John Lee, Kyle Sanchez, Ana Bojorquez-Gomez, Kyle Ford, Brenton P. Munson, Katherine Licon, Sarah Bergendahl, John Paul Shen, Jason F. Kreisberg, Prashant Mali, Jeffrey H. Hager, Michael A. White, Trey Ideker
{"title":"Author Correction: A multilineage screen identifies actionable synthetic lethal interactions in human cancers","authors":"Samson H. Fong, Brent M. Kuenzi, Nicole M. Mattson, John Lee, Kyle Sanchez, Ana Bojorquez-Gomez, Kyle Ford, Brenton P. Munson, Katherine Licon, Sarah Bergendahl, John Paul Shen, Jason F. Kreisberg, Prashant Mali, Jeffrey H. Hager, Michael A. White, Trey Ideker","doi":"10.1038/s41588-025-02090-9","DOIUrl":"10.1038/s41588-025-02090-9","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 2","pages":"480-480"},"PeriodicalIF":31.7,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-025-02090-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142989895","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 : 2025-01-15DOI: 10.1038/s41588-024-02062-5
Michael Fletcher
{"title":"Nucleotide-resolution DNA foundation models of prokaryotic genomes","authors":"Michael Fletcher","doi":"10.1038/s41588-024-02062-5","DOIUrl":"10.1038/s41588-024-02062-5","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 1","pages":"2-2"},"PeriodicalIF":31.7,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142986744","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 : 2025-01-15DOI: 10.1038/s41588-024-02060-7
Safia Danovi
{"title":"Mutations in healthy breast tissue","authors":"Safia Danovi","doi":"10.1038/s41588-024-02060-7","DOIUrl":"10.1038/s41588-024-02060-7","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 1","pages":"2-2"},"PeriodicalIF":31.7,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142986745","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 : 2025-01-14DOI: 10.1038/s41588-024-02057-2
Ya Cui, Frederick J. Arnold, Jason Sheng Li, Jie Wu, Dan Wang, Julien Philippe, Michael R. Colwin, Sebastian Michels, Chaorong Chen, Tamer Sallam, Leslie M. Thompson, Albert R. La Spada, Wei Li
Tandem repeat (TR) size variation is implicated in ~50 neurological disorders, yet its impact on gene regulation in the human brain remains largely unknown. In the present study, we quantified the impact of TR size variation on brain gene regulation across distinct molecular phenotypes, based on 4,412 multi-omics samples from 1,597 donors, including 1,586 newly sequenced ones. We identified ~2.2 million TR molecular quantitative trait loci (TR-xQTLs), linking ~139,000 unique TRs to nearby molecular phenotypes, including many known disease-risk TRs, such as the G2C4 expansion in C9orf72 associated with amyotrophic lateral sclerosis. Fine-mapping revealed ~18,700 TRs as potential causal variants. Our in vitro experiments further confirmed the causal and independent regulatory effects of three TRs. Additional colocalization analysis indicated the potential causal role of TR variation in brain-related phenotypes, highlighted by a 3ʹ-UTR TR in NUDT14 linked to cortical surface area and a TG repeat in PLEKHA1, associated with Alzheimer’s disease. Mapping of multi-omic molecular quantitative trait loci associated with tandem repeat size variation in up to 4,412 human brain samples from 1,597 donors offers insights into how these variants affect gene regulation and mediate disease risk.
{"title":"Multi-omic quantitative trait loci link tandem repeat size variation to gene regulation in human brain","authors":"Ya Cui, Frederick J. Arnold, Jason Sheng Li, Jie Wu, Dan Wang, Julien Philippe, Michael R. Colwin, Sebastian Michels, Chaorong Chen, Tamer Sallam, Leslie M. Thompson, Albert R. La Spada, Wei Li","doi":"10.1038/s41588-024-02057-2","DOIUrl":"10.1038/s41588-024-02057-2","url":null,"abstract":"Tandem repeat (TR) size variation is implicated in ~50 neurological disorders, yet its impact on gene regulation in the human brain remains largely unknown. In the present study, we quantified the impact of TR size variation on brain gene regulation across distinct molecular phenotypes, based on 4,412 multi-omics samples from 1,597 donors, including 1,586 newly sequenced ones. We identified ~2.2 million TR molecular quantitative trait loci (TR-xQTLs), linking ~139,000 unique TRs to nearby molecular phenotypes, including many known disease-risk TRs, such as the G2C4 expansion in C9orf72 associated with amyotrophic lateral sclerosis. Fine-mapping revealed ~18,700 TRs as potential causal variants. Our in vitro experiments further confirmed the causal and independent regulatory effects of three TRs. Additional colocalization analysis indicated the potential causal role of TR variation in brain-related phenotypes, highlighted by a 3ʹ-UTR TR in NUDT14 linked to cortical surface area and a TG repeat in PLEKHA1, associated with Alzheimer’s disease. Mapping of multi-omic molecular quantitative trait loci associated with tandem repeat size variation in up to 4,412 human brain samples from 1,597 donors offers insights into how these variants affect gene regulation and mediate disease risk.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 2","pages":"369-378"},"PeriodicalIF":31.7,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142974575","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}
Rice production is facing substantial threats from global warming associated with extreme temperatures. Here we report that modifying a heat stress-induced negative regulator, a negative regulator of thermotolerance 1 (NAT1), increases wax deposition and enhances thermotolerance in rice. We demonstrated that the C2H2 family transcription factor NAT1 directly inhibits bHLH110 expression, and bHLH110 directly promotes the expression of wax biosynthetic genes CER1/CER1L under heat stress conditions. In situ hybridization revealed that both NAT1 and bHLH110 are predominantly expressed in epidermal layers. By using gene-editing technology, we successfully mutated NAT1 to eliminate its inhibitory effects on wax biosynthesis and improved thermotolerance without yield penalty under normal temperature conditions. Field trials further confirmed the potential of NAT1-edited rice to increase seed-setting rate and grain yield. Therefore, our findings shed light on the regulatory mechanisms governing wax biosynthesis under heat stress conditions in rice and provide a strategy to enhance heat resilience through the modification of NAT1. Negative regulator of thermotolerance 1 (NAT1) is identified as a negative regulator of thermotolerance in rice through the NAT1–bHLH110–CER1/CER1L module. Modifying NAT1 by targeted gene editing increases wax deposition and enhances thermotolerance in rice.
水稻生产正面临着与极端温度相关的全球变暖的重大威胁。本文报道了对热胁迫诱导的负调节因子——耐热性负调节因子NAT1 （negative regulator of thermotolerance 1, NAT1）进行修饰，可以增加水稻的蜡沉积，增强其耐热性。我们证明了C2H2家族转录因子NAT1直接抑制bHLH110的表达，bHLH110在热应激条件下直接促进蜡质生物合成基因CER1/CER1L的表达。原位杂交结果显示，NAT1和bHLH110主要表达于表皮层。通过基因编辑技术，我们成功突变了NAT1，消除了其对蜡生物合成的抑制作用，提高了常温条件下的耐热性，且产量不受影响。田间试验进一步证实了nat1编辑水稻在提高结实率和籽粒产量方面的潜力。因此，我们的研究结果揭示了水稻在热胁迫条件下蜡质生物合成的调控机制，并提供了通过修饰NAT1来增强耐热性的策略。
{"title":"The NAT1–bHLH110–CER1/CER1L module regulates heat stress tolerance in rice","authors":"Hai-Ping Lu, Xue-Huan Liu, Mei-Jing Wang, Qiao-Yun Zhu, Yu-Shu Lyu, Jian-Hang Xu, Jian-Xiang Liu","doi":"10.1038/s41588-024-02065-2","DOIUrl":"10.1038/s41588-024-02065-2","url":null,"abstract":"Rice production is facing substantial threats from global warming associated with extreme temperatures. Here we report that modifying a heat stress-induced negative regulator, a negative regulator of thermotolerance 1 (NAT1), increases wax deposition and enhances thermotolerance in rice. We demonstrated that the C2H2 family transcription factor NAT1 directly inhibits bHLH110 expression, and bHLH110 directly promotes the expression of wax biosynthetic genes CER1/CER1L under heat stress conditions. In situ hybridization revealed that both NAT1 and bHLH110 are predominantly expressed in epidermal layers. By using gene-editing technology, we successfully mutated NAT1 to eliminate its inhibitory effects on wax biosynthesis and improved thermotolerance without yield penalty under normal temperature conditions. Field trials further confirmed the potential of NAT1-edited rice to increase seed-setting rate and grain yield. Therefore, our findings shed light on the regulatory mechanisms governing wax biosynthesis under heat stress conditions in rice and provide a strategy to enhance heat resilience through the modification of NAT1. Negative regulator of thermotolerance 1 (NAT1) is identified as a negative regulator of thermotolerance in rice through the NAT1–bHLH110–CER1/CER1L module. Modifying NAT1 by targeted gene editing increases wax deposition and enhances thermotolerance in rice.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 2","pages":"427-440"},"PeriodicalIF":31.7,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142975171","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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