SETD2 loss-of-function uniquely sensitizes cells to epigenetic targeting of NSD1-directed H3K36 methylation
Abstract Background SETD2 is the sole epigenetic factor responsible for catalyzing histone 3, lysine 36, tri-methylation (H3K36me3) in mammals. Its role in regulating cellular processes such as RNA splicing, DNA repair, and spurious transcription initiation underlies its broader tumor suppressor fun...
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BMC
2025-02-01
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| Series: | Genome Biology |
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| Online Access: | https://doi.org/10.1186/s13059-025-03483-z |
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| author | Ryan T. Wagner Ryan A. Hlady Xiaoyu Pan Liguo Wang Sungho Kim Xia Zhao Louis Y. El Khoury Shafiq Shaikh Jian Zhong Jeong-Heon Lee Jolanta Grembecka Tomasz Cierpicki Thai H. Ho Keith D. Robertson |
| author_facet | Ryan T. Wagner Ryan A. Hlady Xiaoyu Pan Liguo Wang Sungho Kim Xia Zhao Louis Y. El Khoury Shafiq Shaikh Jian Zhong Jeong-Heon Lee Jolanta Grembecka Tomasz Cierpicki Thai H. Ho Keith D. Robertson |
| author_sort | Ryan T. Wagner |
| collection | DOAJ |
| description | Abstract Background SETD2 is the sole epigenetic factor responsible for catalyzing histone 3, lysine 36, tri-methylation (H3K36me3) in mammals. Its role in regulating cellular processes such as RNA splicing, DNA repair, and spurious transcription initiation underlies its broader tumor suppressor function. SETD2 mutation promotes the epithelial-mesenchymal transition and is clinically associated with adverse outcomes highlighting a therapeutic need to develop targeted therapies against this dangerous mutation. Results We employ an unbiased genome-wide synthetic lethal screen, which identifies another H3K36me writer, NSD1, as a synthetic lethal modifier in SETD2-mutant cells. Confirmation of this synthetic lethal interaction is performed in isogenic clear cell renal cell carcinoma and immortalized renal epithelial cell lines, in mouse and human backgrounds. Depletion of NSD1 using a CRISPRi targeting approach promotes the loss of SETD2-mutant cells coincident with elevated levels of DNA damage and apoptosis. Surprisingly, only suppression of NSD1, but not related H3K36-methyltransferases, promotes synthetic lethality in these models. Mapping of genomic H3K36me2 targeting by NSD1 and NSD2 individually highlights the independent functions of these epigenetic writers. Furthermore, as a proof-of-principle, we demonstrate the therapeutic feasibility of targeting this synthetic lethal interaction by recapitulating the phenotype using BT5, a first-in-class pharmacologic inhibitor against NSD1. Conclusions These findings unify genome-wide screening approaches with the latest genetic and pharmacologic modeling methodologies to reveal an entirely novel epigenetic approach to individualize therapies against a challenging loss-of-function SETD2 mutation in cancer. |
| format | Article |
| id | doaj-art-0b5aff09696c425c9be500dbdf2abc4e |
| institution | Kabale University |
| issn | 1474-760X |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Biology |
| spelling | doaj-art-0b5aff09696c425c9be500dbdf2abc4e2025-02-09T12:39:21ZengBMCGenome Biology1474-760X2025-02-0126112810.1186/s13059-025-03483-zSETD2 loss-of-function uniquely sensitizes cells to epigenetic targeting of NSD1-directed H3K36 methylationRyan T. Wagner0Ryan A. Hlady1Xiaoyu Pan2Liguo Wang3Sungho Kim4Xia Zhao5Louis Y. El Khoury6Shafiq Shaikh7Jian Zhong8Jeong-Heon Lee9Jolanta Grembecka10Tomasz Cierpicki11Thai H. Ho12Keith D. Robertson13Department of Molecular Pharmacology and Experimental Therapeutics, Mayo ClinicDepartment of Molecular Pharmacology and Experimental Therapeutics, Mayo ClinicDepartment of Molecular Pharmacology and Experimental Therapeutics, Mayo ClinicDivision of Computational Biology, Mayo Clinic College of Medicine and ScienceDepartment of Molecular Pharmacology and Experimental Therapeutics, Mayo ClinicDepartment of Molecular Pharmacology and Experimental Therapeutics, Mayo ClinicDepartment of Molecular Pharmacology and Experimental Therapeutics, Mayo ClinicDepartment of Obstetrics and Gynecology, Medical College of WisconsinEpigenomics Development Laboratory, Mayo ClinicEpigenomics Development Laboratory, Mayo ClinicDepartment of Pathology, University of MichiganDepartment of Pathology, University of MichiganDivision of Hematology and Oncology, Hollings Cancer Center, Medical University of South CarolinaDepartment of Molecular Pharmacology and Experimental Therapeutics, Mayo ClinicAbstract Background SETD2 is the sole epigenetic factor responsible for catalyzing histone 3, lysine 36, tri-methylation (H3K36me3) in mammals. Its role in regulating cellular processes such as RNA splicing, DNA repair, and spurious transcription initiation underlies its broader tumor suppressor function. SETD2 mutation promotes the epithelial-mesenchymal transition and is clinically associated with adverse outcomes highlighting a therapeutic need to develop targeted therapies against this dangerous mutation. Results We employ an unbiased genome-wide synthetic lethal screen, which identifies another H3K36me writer, NSD1, as a synthetic lethal modifier in SETD2-mutant cells. Confirmation of this synthetic lethal interaction is performed in isogenic clear cell renal cell carcinoma and immortalized renal epithelial cell lines, in mouse and human backgrounds. Depletion of NSD1 using a CRISPRi targeting approach promotes the loss of SETD2-mutant cells coincident with elevated levels of DNA damage and apoptosis. Surprisingly, only suppression of NSD1, but not related H3K36-methyltransferases, promotes synthetic lethality in these models. Mapping of genomic H3K36me2 targeting by NSD1 and NSD2 individually highlights the independent functions of these epigenetic writers. Furthermore, as a proof-of-principle, we demonstrate the therapeutic feasibility of targeting this synthetic lethal interaction by recapitulating the phenotype using BT5, a first-in-class pharmacologic inhibitor against NSD1. Conclusions These findings unify genome-wide screening approaches with the latest genetic and pharmacologic modeling methodologies to reveal an entirely novel epigenetic approach to individualize therapies against a challenging loss-of-function SETD2 mutation in cancer.https://doi.org/10.1186/s13059-025-03483-zClear cell renal cell carcinoma (ccRCC)SETD2Histone 3, lysine 36, tri-methylation (H3K36me3)NSD1Synthetic lethality (SL)CRISPRi |
| spellingShingle | Ryan T. Wagner Ryan A. Hlady Xiaoyu Pan Liguo Wang Sungho Kim Xia Zhao Louis Y. El Khoury Shafiq Shaikh Jian Zhong Jeong-Heon Lee Jolanta Grembecka Tomasz Cierpicki Thai H. Ho Keith D. Robertson SETD2 loss-of-function uniquely sensitizes cells to epigenetic targeting of NSD1-directed H3K36 methylation Genome Biology Clear cell renal cell carcinoma (ccRCC) SETD2 Histone 3, lysine 36, tri-methylation (H3K36me3) NSD1 Synthetic lethality (SL) CRISPRi |
| title | SETD2 loss-of-function uniquely sensitizes cells to epigenetic targeting of NSD1-directed H3K36 methylation |
| title_full | SETD2 loss-of-function uniquely sensitizes cells to epigenetic targeting of NSD1-directed H3K36 methylation |
| title_fullStr | SETD2 loss-of-function uniquely sensitizes cells to epigenetic targeting of NSD1-directed H3K36 methylation |
| title_full_unstemmed | SETD2 loss-of-function uniquely sensitizes cells to epigenetic targeting of NSD1-directed H3K36 methylation |
| title_short | SETD2 loss-of-function uniquely sensitizes cells to epigenetic targeting of NSD1-directed H3K36 methylation |
| title_sort | setd2 loss of function uniquely sensitizes cells to epigenetic targeting of nsd1 directed h3k36 methylation |
| topic | Clear cell renal cell carcinoma (ccRCC) SETD2 Histone 3, lysine 36, tri-methylation (H3K36me3) NSD1 Synthetic lethality (SL) CRISPRi |
| url | https://doi.org/10.1186/s13059-025-03483-z |
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