Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The C-terminal of NSD2 regulates transcription of cell adhesion genes in multiple myeloma [NS2733_CHIPSEQ]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE274234 | GEO | 2025/01/15

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

The C-terminal of NSD2 regulates transcription of cell adhesion genes in multiple myeloma

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

The C-terminal of NSD2 regulates transcription of cell adhesion genes in multiple myeloma [GE5289_RNASEQ]

2025-01-15 | GSE274233 | GEO

Gene expression profiling of KMS11 parental (PAR), TKO and 8 reconstituted lines

Project description:NSD2, a histone lysine methyltransferase, is overexpressed as a result of the t(4;14) translocation that is associated with 15-20% of multiple myeloma. Earlier studies have indicated that NSD2 may be involved in myelomagenesis and suggested that it may be a target for myeloma therapy. Here we show that NSD2 is required for clonogenic growth, adherence and proliferation on bone marrow stroma, and tumorigenesis of t(4;14)+ but not t(4;14)- myeloma cells, in a methyltransferase activity dependent manner. Furthermore, we found that PHD domains are important for NSD2 cellular activity and biological functions by recruiting it to oncogenic gene loci and driving downstream transcription activation events. These results strengthened the disease link of NSD2 and provided a basis that targeting NSD2 may be a therapeutic strategy in multiple myeloma patients with t(4;14) translocation. Our data also revealed multiple domains in the protein for possible chemical modulation. To elucidate the mechanisms underlying the oncogenic potential of NSD2 in myeloma, we performed microarray analysis on KMS11 parental (PAR), TKO and 8 reconstituted lines. Based on the whole-genome expression profile, the 10 samples clearly fell into 4 clusters – (1) PAR; (2) TKO; (3) WT, WT+MMSET I, 526-1240 and 526-1365; and (4) CDM, CDM+MMSET I, MMSET I and H762Y Biological triplicates of cell cultures of indicated lines were harvested in TRIzol (Invitrogen) and characterized by human U133 plus 2.0 Affymetrix GeneChip. The gene expression data was normalized using the Robust Multiarray Averaging (RMA) method and log2 transformed before comparisons.

2013-08-22 | E-GEOD-50072 | biostudies-arrayexpress

Gene expression profiling of KMS11 parental (PAR), TKO and 8 reconstituted lines

2013-08-22 | GSE50072 | GEO

MMSET regulation of gene expression in t(4;14)+ myeloma

2014-09-01 | GSE57863 | GEO

NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming [RNAi]

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

NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming [Transduction]

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

NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming [TKO]

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

MMSET regulation of gene expression in t(4;14)+ myeloma

Project description:We investigated gene expression in isogenic myeloma cell lines with or without overexpressed MMSET protein. MMSET is a histone methyltransferase which methylates lysine 36 on histone H3. Overexpression of MMSET in myeloma leads to a global increase in H3K36 methylation and concomitant decrease in H3K27 methylation. These global changes in histone methylation lead to altered gene expression. Total RNA was extracted from parental KMS11 cell line, NTKO cells which have the wild type MMSET allele inactivated and TKO cells which have overexpressed MMSET allele inactivated. Two different TKO clones were tested. Each sample was analyzed in triplicate.

2014-09-01 | E-GEOD-57863 | biostudies-arrayexpress

NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming [ChIP]

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

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data