SETD2 loss-of-function uniquely sensitizes cells to epigenetic targeting of NSD1-directed H3K36 methylation.
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ABSTRACT:
PROVIDER: PRJNA1173660 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31015700_1.fastq.gz | Fastqsanger.gz | |||
| SRR31015700_2.fastq.gz | Fastqsanger.gz | |||
| SRR31015701_1.fastq.gz | Fastqsanger.gz | |||
| SRR31015701_2.fastq.gz | Fastqsanger.gz | |||
| SRR31015702_1.fastq.gz | Fastqsanger.gz |
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Project description:SETD2 loss-of-function uniquely sensitizes cells to epigenetic targeting of NSD1-directed H3K36 methylation
| PRJNA1171447 | ENA
Project description:SETD2 is the sole epigenetic factor responsible for catalyzing histone 3, lysine 36, tri-methylation (H3K36me3) in mammals. Its role in regulating diverse cellular processes such as RNA splicing, DNA repair, and spurious transcription underlie its broader tumor suppressor function, which has been detailed in a multitude of cancer types. SETD2 mutation, and by extension loss of H3K36me3, promotes the epithelial-mesenchymal transition (EMT) and is clinically associated with adverse outcomes highlighting a therapeutic need to develop targeted therapies against this dangerous mutation. To this end we employed an unbiased genome-wide synthetic lethal screen, which identified another H3K36me writer, NSD1, as a synthetic lethal modifier in SETD2-mutant cells. Confirmation of this synthetic lethal interaction was performed via modeling in isogenic clear cell renal cell carcinoma (ccRCC ) cell lines. Depletion of NSD1 using a CRISPRi targeting approach promoted the loss of SETD2-mutant cells coincident with elevated DNA damage and apoptosis. Surprisingly, only suppression of NSD1, and not the related H3K36-methyltransferases NSD2 or NSD3, promoted synthetic lethality (SL) in these models. Further investigation of H3K36me2 targeting by NSD1 and NSD2 respectively highlight 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 a first-of-its kind pharmacologic inhibitor against NSD1 (BT5). Notably, these findings unify unbiased genome-wide screening approaches with the latest genetic and pharmacologic modeling methodologies to reveal an entirely novel epigenetic approach in the advancement of individualized therapies for the treatment of SETD2-mutant cancer.
2025-01-17 | GSE279619 | GEO
Project description:SETD2 is the sole epigenetic factor responsible for catalyzing histone 3, lysine 36, tri-methylation (H3K36me3) in mammals. Its role in regulating diverse cellular processes such as RNA splicing, DNA repair, and spurious transcription underlie its broader tumor suppressor function, which has been detailed in a multitude of cancer types. SETD2 mutation, and by extension loss of H3K36me3, promotes the epithelial-mesenchymal transition (EMT) and is clinically associated with adverse outcomes highlighting a therapeutic need to develop targeted therapies against this dangerous mutation. To this end we employed an unbiased genome-wide synthetic lethal screen, which identified another H3K36me writer, NSD1, as a synthetic lethal modifier in SETD2-mutant cells. Confirmation of this synthetic lethal interaction was performed via modeling in isogenic clear cell renal cell carcinoma (ccRCC ) cell lines. Depletion of NSD1 using a CRISPRi targeting approach promoted the loss of SETD2-mutant cells coincident with elevated DNA damage and apoptosis. Surprisingly, only suppression of NSD1, and not the related H3K36-methyltransferases NSD2 or NSD3, promoted synthetic lethality (SL) in these models. Further investigation of H3K36me2 targeting by NSD1 and NSD2 respectively highlight 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 a first-of-its kind pharmacologic inhibitor against NSD1 (BT5). Notably, these findings unify unbiased genome-wide screening approaches with the latest genetic and pharmacologic modeling methodologies to reveal an entirely novel epigenetic approach in the advancement of individualized therapies for the treatment of SETD2-mutant cancer.
2025-01-17 | GSE279234 | GEO
Project description:SETD2 is the sole epigenetic factor responsible for catalyzing histone 3, lysine 36, tri-methylation (H3K36me3) in mammals. Its role in regulating diverse cellular processes such as RNA splicing, DNA repair, and spurious transcription underlie its broader tumor suppressor function, which has been detailed in a multitude of cancer types. SETD2 mutation, and by extension loss of H3K36me3, promotes the epithelial-mesenchymal transition (EMT) and is clinically associated with adverse outcomes highlighting a therapeutic need to develop targeted therapies against this dangerous mutation. To this end we employed an unbiased genome-wide synthetic lethal screen, which identified another H3K36me writer, NSD1, as a synthetic lethal modifier in SETD2-mutant cells. Confirmation of this synthetic lethal interaction was performed via modeling in isogenic clear cell renal cell carcinoma (ccRCC ) cell lines. Depletion of NSD1 using a CRISPRi targeting approach promoted the loss of SETD2-mutant cells coincident with elevated DNA damage and apoptosis. Surprisingly, only suppression of NSD1, and not the related H3K36-methyltransferases NSD2 or NSD3, promoted synthetic lethality (SL) in these models. Further investigation of H3K36me2 targeting by NSD1 and NSD2 respectively highlight 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 a first-of-its kind pharmacologic inhibitor against NSD1 (BT5). Notably, these findings unify unbiased genome-wide screening approaches with the latest genetic and pharmacologic modeling methodologies to reveal an entirely novel epigenetic approach in the advancement of individualized therapies for the treatment of SETD2-mutant cancer.
2025-01-17 | GSE279442 | GEO
Project description:SETD2 loss-of-function uniquely sensitizes cells to epigenetic targeting of NSD1-directed H3K36 methylation [RNA-seq]
| PRJNA1172716 | ENA
Project description:BackgroundSETD2 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.ResultsWe 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.ConclusionsThese 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.
| S-EPMC11800516 | biostudies-literature
Project description:Methylation of histone 3 lysine 36 (H3K36me) has emerged as an essential epigenetic component for the faithful regulation of gene expression. Despite its demonstrated importance in development, disease, and cancer, the molecular agents responsible for the deposition of H3K36me are not yet well understood. Here, we use a mouse mesenchymal stem cell model to comprehensively perturb the components of the H3K36me deposition machinery and infer the activities of the five most prominent players: SETD2, NSD1, NSD2, NSD3, and ASH1L. We find that H3K36me2 is the most abundant of the three methylation states and that it is predominantly deposited at intergenic regions by NSD1, and in part by NSD2. In contrast, H3K36me1/3 are most abundant within exons and have a positive correlation with gene expression. We further demonstrate that while SETD2 is responsible for depositing most H3K36me3, it also deposits a modest amount of H3K36me2 within transcribed genes. Additionally, loss of SETD2 results in an increase of exonic H3K36me1, suggesting that other H3K36 methyltransferases may prime gene bodies with lower methylation states ahead of transcription. Through a reductive approach, we uncover the genome-wide distribution patterns of NSD3- and ASH1L-catalyzed H3K36me2. While NSD1/2 establish broad intergenic H3K36me2 domains, NSD3 deposits broad H3K36me2 peaks centered on active promoter and enhancer regions. Meanwhile, the activity of ASH1L is focused primarily on the promoters of developmentally relevant genes, and our analyses implicate PBX2 as a potential recruitment factor for ASH1L to these regions. Overall, our study provides new insights into the regulation of H3K36me by the H3K36 methyltransferase family and helps to consolidate the wealth of previous observations in the context of a structured analysis.
2023-10-05 | MSV000093049 | MassIVE
Project description:Nuclear receptor-binding SET domain protein 1 (NSD1) prototype is a family of mammalian histone methyltransferases (NSD1, NSD2/MMSET/WHSC1, NSD3/WHSC1L1) that are essential in development and are mutated in human acute myeloid leukemia (AML), overgrowth syndromes, multiple myeloma and lung cancers. In AML, the recurring t(5;11)(q35;p15.5) translocation fuses NSD1 to nucleoporin-98 (NUP98). Here, we present the first characterization of the transforming properties and molecular mechanisms of NUP98-NSD1. We demonstrate that NUP98-NSD1 induces AML in vivo, sustains self-renewal of myeloid stem cells in vitro, and enforces expression of the HoxA7, HoxA9, HoxA10 and Meis1 proto-oncogenes. Mechanistically, NUP98-NSD1 binds genomic elements adjacent to HoxA7 and HoxA9, maintains histone H3 Lys 36 (H3K36) methylation and histone acetylation, and prevents EZH2-mediated transcriptional repression of the Hox-A locus during differentiation. Deletion of the NUP98 FG-repeat domain, or mutations in NSD1 that inactivate the H3K36 methyltransferase activity or that prevent binding of NUP98-NSD1 to the Hox-A locus precluded both Hox-A gene activation and myeloid progenitor immortalization. We propose that NUP98-NSD1 prevents EZH2-mediated repression of Hox-A locus genes by colocalizing H3K36 methylation and histone acetylation at regulatory DNA elements. This report is the first to link deregulated H3K36 methylation to tumorigenesis and to link NSD1 to transcriptional regulation of the Hox-A locus. Experiment Overall Design: Total RNA was extracted from stably transformed progenitors cultured in vitro and the expression levels of mRNA transcripts quantified using the Affymetrix GeneChip Mouse Genome 430 2.0 array, as previously described. The GEO database accession numbers: for progenitors immortalized by HoxA9 (GSM190542, GSM190546, GSM190547); for progenitors immortalized by coexpressed HoxA9 plus Meis1 (GSM190548, GSM190549, GSM190550); for progenitors immortalized by NUP98-NSD1 (GSM190551, GSM190552, GSM190553); and for progenitors immortalized by MLL-ENL (GSM190554). Experiment Overall Design: NOTE: CEL files and dChip data were requested by GEO but not provided.
2008-06-11 | E-GEOD-10071 | biostudies-arrayexpress
Project description:Methylation of histone 3 lysine 36 (H3K36me) has emerged as an essential epigenetic component for the faithful regulation of gene expression. Despite its importance in development, disease, and cancer, how the molecular agents collectively shape the genome-wide deposition of H3K36me is unclear. Here, we use mouse mesenchymal stem cells to comprehensively perturb the components of the H3K36me deposition machinery and infer the activities of the five most prominent players: SETD2, NSD1, NSD2, NSD3, and ASH1L. We find that H3K36me2 is the most abundant of the three methylation states and that it is predominantly deposited at intergenic regions by NSD1, and in part by NSD2. In contrast, H3K36me1/3 are most abundant within exons and are positively correlated with gene expression. We demonstrate that while SETD2 is responsible for depositing most H3K36me3, it also deposits H3K36me2 within transcribed genes. Additionally, loss of SETD2 results in an increase of exonic H3K36me1, suggesting that other H3K36 methyltransferases may prime gene bodies with lower methylation states ahead of transcription. Through a reductive approach, we uncover the distribution patterns of NSD3- and ASH1L-catalyzed H3K36me2. While NSD1/2 establish broad intergenic H3K36me2 domains, NSD3 deposits H3K36me2 peaks centered on active promoter and enhancer regions. Meanwhile, the activity of ASH1L is restricted to regulatory elements of developmentally relevant genes, and our analyses implicate PBX2 as a potential recruitment factor. Overall, our study provides new insights into the regulation of H3K36me and helps to consolidate the wealth of previous observations in the context of structured analyses.
2024-09-25 | GSE243566 | GEO
Project description:Nuclear receptor-binding SET domain protein 1 (NSD1) prototype is a family of mammalian histone methyltransferases (NSD1, NSD2/MMSET/WHSC1, NSD3/WHSC1L1) that are essential in development and are mutated in human acute myeloid leukemia (AML), overgrowth syndromes, multiple myeloma and lung cancers. In AML, the recurring t(5;11)(q35;p15.5) translocation fuses NSD1 to nucleoporin-98 (NUP98). Here, we present the first characterization of the transforming properties and molecular mechanisms of NUP98-NSD1. We demonstrate that NUP98-NSD1 induces AML in vivo, sustains self-renewal of myeloid stem cells in vitro, and enforces expression of the HoxA7, HoxA9, HoxA10 and Meis1 proto-oncogenes. Mechanistically, NUP98-NSD1 binds genomic elements adjacent to HoxA7 and HoxA9, maintains histone H3 Lys 36 (H3K36) methylation and histone acetylation, and prevents EZH2-mediated transcriptional repression of the Hox-A locus during differentiation. Deletion of the NUP98 FG-repeat domain, or mutations in NSD1 that inactivate the H3K36 methyltransferase activity or that prevent binding of NUP98-NSD1 to the Hox-A locus precluded both Hox-A gene activation and myeloid progenitor immortalization. We propose that NUP98-NSD1 prevents EZH2-mediated repression of Hox-A locus genes by colocalizing H3K36 methylation and histone acetylation at regulatory DNA elements. This report is the first to link deregulated H3K36 methylation to tumorigenesis and to link NSD1 to transcriptional regulation of the Hox-A locus. Keywords: expression analysis
2008-01-04 | GSE10071 | GEO