Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

NSD2 interacts with SMARCA2 and regulates expression of oncogenes CCND1 and PRL3 in t(4;14) multiple myeloma

ABSTRACT: Recurrent chromosomal translocations are central to the pathogenesis of multiple myeloma (MM), with t(4;14) translocation being the second-most common and associated with poor prognosis. The nuclear receptor-binding SET domain 2 (NSD2) is overexpressed as a result of the translocation and has been suggested to be the primary oncogenic factor in t(4;14) MM. However, the detailed oncogenic mechanism of NSD2 in MM is still not completely understood. To address the relevant pathways downstream of NSD2 that contributes to myelomagenesis, SILAC-based mass-spectrometry analysis was used to determine NSD2-interacting proteins. We identified 74 proteins and in silico analysis showed that one of them, SMARCA2, interacts with NSD2. Comparison of SMARCA2 expression across MM cell lines with different translocation statuses showed that SMARCA2 was highly expressed in t(4;14) MM cells but not in non-t(4;14) MM cells. SMARCA2 knockdown in t(4;14) MM cells showed reduced cell growth and capacity to form colonies. We further investigated how NSD2 and SMARCA2 regulate the expressions of key myeloma genes, such as PRL3 and CCND1. This study reveals a spectrum of NSD2-interacting proteins involved in different biological pathways, indicating the importance of NSD2 in t(4;14) MM. The interaction between NSD2 and SMARCA2 in regulating the expression of CCND1 and PRL3 suggests the potential of SMARCA2 as a novel therapeutic target for t(4;14) MM.

ORGANISM(S): Homo sapiens

PROVIDER: GSE140860 | GEO | 2021/07/15

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

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

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

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

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

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

2013-08-22 | GSE50072 | GEO

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

2011-11-29 | GSE29150 | GEO

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

2011-11-29 | GSE29148 | GEO

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

2011-11-29 | GSE29147 | GEO

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

2011-11-29 | GSE29146 | GEO