Aurora kinase A phosphorylates histone methyltransferase NSD2 to promote drug resistance in multiple myeloma [RNA-Seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA686884 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13280451.fastq.gz | Fastqsanger.gz | |||
| SRR13280452.fastq.gz | Fastqsanger.gz | |||
| SRR13280453.fastq.gz | Fastqsanger.gz | |||
| SRR13280454.fastq.gz | Fastqsanger.gz | |||
| SRR13280455.fastq.gz | Fastqsanger.gz |
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Project description:The epigenetic plasticity, such as DNA methylation and histone modification, has been suggested to be a potential mechanism controlling MM progression and drug resistance, but the underlying mechanisms are not fully understood. Here we demonstrate that some drug resistant genes were activated during myeloma resistance to bortezomib. Mechanistically, Aurora A can interact with NSD2, whose SET domain is responsible to H3K36me2 to enhance the transcriptional activity of Aurora A target gene. Once Aurora A is knocked out, H3K36me2 activity will change, changing the transcription activity of those drug resistant genes.
2020-12-22 | GSE163589 | GEO
Project description:NSD2 is a histone methyltransferase that specifically dimethylates histone H3 lysine 36 (H3K36me2), a modification associated with gene activation. Dramatic overexpression of NSD2 in t(4;14) multiple myeloma (MM) and an activating mutation of NSD2 discovered in acute lymphoblastic leukemia (ALL) are significantly associated with altered gene activation, transcription and DNA damage repair. The partner proteins through which NSD2 may influence critical cellular processes remain poorly defined. In this study, we utilized proximity-based labelling (BioID) combined with label-free quantitative mass spectrometry to identify high confidence NSD2 interacting partners in MM cells.
2019-06-27 | PXD013759 | Pride
Project description:NSD2 (also named MMSET and WHSC1) is a histone lysine methyltransferase that is implicated in diverse diseases and commonly overexpressed in multiple myeloma due to a recurrent t(4;14) chromosomal translocation. However, the precise catalytic activity of NSD2 is obscure, preventing progress in understanding how this enzyme influences chromatin biology and myeloma pathogenesis. Here we show that dimethylation of histone H3 at lysine 36 (H3K36me2) is the principal chromatin-regulatory activity of NSD2. Catalysis of H3K36me2 by NSD2 is sufficient for gene activation. In t(4;14)-positive myeloma cells, the normal genome-wide and gene-specific distribution of H3K36me2 is obliterated, creating a chromatin landscape that selects for a transcription profile favorable for myelomagenesis. Catalytically active NSD2 confers xenograft tumor formation and invasion capacity upon t(4;14)-negative cells and NSD2 promotes oncogenic transformation of primary cells in an H3K36me2-dependent manner. Together our findings establish H3K36me2 as the primary product generated by NSD2, and demonstrate that genomic disorganization of this canonical chromatin mark initiates oncogenic programming. Genome-wide expression profiling of KMS11 cells stably transduced with control vector in comparison to two independent shRNAs against NSD2. Each cell line is tested in duplicate.
2011-11-29 | E-GEOD-29147 | biostudies-arrayexpress
Project description:NSD2 (also named MMSET and WHSC1) is a histone lysine methyltransferase that is implicated in diverse diseases and commonly overexpressed in multiple myeloma due to a recurrent t(4;14) chromosomal translocation. However, the precise catalytic activity of NSD2 is obscure, preventing progress in understanding how this enzyme influences chromatin biology and myeloma pathogenesis. Here we show that dimethylation of histone H3 at lysine 36 (H3K36me2) is the principal chromatin-regulatory activity of NSD2. Catalysis of H3K36me2 by NSD2 is sufficient for gene activation. In t(4;14)-positive myeloma cells, the normal genome-wide and gene-specific distribution of H3K36me2 is obliterated, creating a chromatin landscape that selects for a transcription profile favorable for myelomagenesis. Catalytically active NSD2 confers xenograft tumor formation and invasion capacity upon t(4;14)-negative cells and NSD2 promotes oncogenic transformation of primary cells in an H3K36me2-dependent manner. Together our findings establish H3K36me2 as the primary product generated by NSD2, and demonstrate that genomic disorganization of this canonical chromatin mark initiates oncogenic programming. Genome-wide expression profiling of p19ARF-/- mouse embryonic fibroblasts stably transduced with control vector or wild-type NSD2. Each cell line is tested in triplicate.
2011-11-29 | E-GEOD-29150 | biostudies-arrayexpress
Project description:NSD2 (also named MMSET and WHSC1) is a histone lysine methyltransferase that is implicated in diverse diseases and commonly overexpressed in multiple myeloma due to a recurrent t(4;14) chromosomal translocation. However, the precise catalytic activity of NSD2 is obscure, preventing progress in understanding how this enzyme influences chromatin biology and myeloma pathogenesis. Here we show that dimethylation of histone H3 at lysine 36 (H3K36me2) is the principal chromatin-regulatory activity of NSD2. Catalysis of H3K36me2 by NSD2 is sufficient for gene activation. In t(4;14)-positive myeloma cells, the normal genome-wide and gene-specific distribution of H3K36me2 is obliterated, creating a chromatin landscape that selects for a transcription profile favorable for myelomagenesis. Catalytically active NSD2 confers xenograft tumor formation and invasion capacity upon t(4;14)-negative cells and NSD2 promotes oncogenic transformation of primary cells in an H3K36me2-dependent manner. Together our findings establish H3K36me2 as the primary product generated by NSD2, and demonstrate that genomic disorganization of this canonical chromatin mark initiates oncogenic programming. Genome-wide expression profiling of KMS11 and t(4;14) translocation knockout (TKO) cells. Each cell line is tested in triplicate.
2011-11-29 | E-GEOD-29148 | biostudies-arrayexpress
Project description:NSD2 (also named MMSET and WHSC1) is a histone lysine methyltransferase that is implicated in diverse diseases and commonly overexpressed in multiple myeloma due to a recurrent t(4;14) chromosomal translocation. However, the precise catalytic activity of NSD2 is obscure, preventing progress in understanding how this enzyme influences chromatin biology and myeloma pathogenesis. Here we show that dimethylation of histone H3 at lysine 36 (H3K36me2) is the principal chromatin-regulatory activity of NSD2. Catalysis of H3K36me2 by NSD2 is sufficient for gene activation. In t(4;14)-positive myeloma cells, the normal genome-wide and gene-specific distribution of H3K36me2 is obliterated, creating a chromatin landscape that selects for a transcription profile favorable for myelomagenesis. Catalytically active NSD2 confers xenograft tumor formation and invasion capacity upon t(4;14)-negative cells and NSD2 promotes oncogenic transformation of primary cells in an H3K36me2-dependent manner. Together our findings establish H3K36me2 as the primary product generated by NSD2, and demonstrate that genomic disorganization of this canonical chromatin mark initiates oncogenic programming. ChIP sequencing of H3K36me2 ChIP DNA from KMS11 and TKO2 cells using Illumina Solexa Genome Analyzer II single end sequencing protocol. The experiment contains two biological replicates of H3K36me2 ChIP DNA and input materials from KMS11 and TKO2 cells.
2011-11-29 | E-GEOD-29146 | biostudies-arrayexpress
Project description:The overexpression of the histone methyltransferase NSD2 (MMSET) in multiple myeloma (MM) patients plays a significant role in the development of this specific subtype of disease. Through the expansion of gene activation associated H3K36me2 and suppression of repressive H3K27me3 marks, NSD2 activates an aberrant set of genes that contribute to myeloma growth adhesive and invasive activities. NSD2 transcriptional activity also depends on its non-catalytic domains, which facilitate its recruitment to chromatin through histone binding. In this study, using NMR and ITC techniques, we demonstrate that the tandem PHD domain of NSD2 (PHDvC5HCHNSD2) acts as a reader for both unmodified histone H3K4 and three-methylated H3K27, making it the first PHD tandem cassette known to decode the methylation status of H3K27. We present a three-dimensional model of the complex based on NMR data and molecular dynamics simulations. Importantly, expression of mutants of PHDvC5HCHNSD2, designed to impair binding to the histone H3 tail in NSD2 deficient cells, leads to decreased activation of adhesive properties and cell adhesion genes and a decrease in corresponding H3K27ac signal at promoters. Moreover, expression of PHDvC5HCH mutant forms of NSD2 result in incomplete loss of H3K27 methylation throughout the genome compared to expression of wild-type NSD2. Collectively, these data indicate that PHDvC5HCH of NSD2 plays an important role in modulating gene expression and chromatin modification, thus opening new opportunities for pharmacological intervention.
2025-01-15 | GSE274250 | GEO
Project description:Aurora-A phosphorylates splicing factors and regulates alternative splicing
| PRJNA674315 | ENA
Project description:The overexpression of the histone methyltransferase NSD2 (MMSET) in multiple myeloma (MM) patients plays a significant role in the development of this specific subtype of disease. Through the expansion of gene activation associated H3K36me2 and suppression of repressive H3K27me3 marks, NSD2 activates an aberrant set of genes that contribute to myeloma growth adhesive and invasive activities. NSD2 transcriptional activity also depends on its non-catalytic domains, which facilitate its recruitment to chromatin through histone binding. In this study, using NMR and ITC techniques, we demonstrate that the tandem PHD domain of NSD2 (PHDvC5HCHNSD2) acts as a reader for both unmodified histone H3K4 and three-methylated H3K27, making it the first PHD tandem cassette known to decode the methylation status of H3K27. We present a three-dimensional model of the complex based on NMR data and molecular dynamics simulations. Importantly, expression of mutants of PHDvC5HCHNSD2, designed to impair binding to the histone H3 tail in NSD2 deficient cells, leads to decreased activation of adhesive properties and cell adhesion genes and a decrease in corresponding H3K27ac signal at promoters. Moreover, expression of PHDvC5HCH mutant forms of NSD2 result in incomplete loss of H3K27 methylation throughout the genome compared to expression of wild-type NSD2. Collectively, these data indicate that PHDvC5HCH of NSD2 plays an important role in modulating gene expression and chromatin modification, thus opening new opportunities for pharmacological intervention.
2025-01-15 | GSE274234 | GEO
Project description:The overexpression of the histone methyltransferase NSD2 (MMSET) in multiple myeloma (MM) patients plays a significant role in the development of this specific subtype of disease. Through the expansion of gene activation associated H3K36me2 and suppression of repressive H3K27me3 marks, NSD2 activates an aberrant set of genes that contribute to myeloma growth adhesive and invasive activities. NSD2 transcriptional activity also depends on its non-catalytic domains, which facilitate its recruitment to chromatin through histone binding. In this study, using NMR and ITC techniques, we demonstrate that the tandem PHD domain of NSD2 (PHDvC5HCHNSD2) acts as a reader for both unmodified histone H3K4 and three-methylated H3K27, making it the first PHD tandem cassette known to decode the methylation status of H3K27. We present a three-dimensional model of the complex based on NMR data and molecular dynamics simulations. Importantly, expression of mutants of PHDvC5HCHNSD2, designed to impair binding to the histone H3 tail in NSD2 deficient cells, leads to decreased activation of adhesive properties and cell adhesion genes and a decrease in corresponding H3K27ac signal at promoters. Moreover, expression of PHDvC5HCH mutant forms of NSD2 result in incomplete loss of H3K27 methylation throughout the genome compared to expression of wild-type NSD2. Collectively, these data indicate that PHDvC5HCH of NSD2 plays an important role in modulating gene expression and chromatin modification, thus opening new opportunities for pharmacological intervention.
2025-01-15 | GSE274233 | GEO