MMSET regulation of gene expression in t(4;14)+ myeloma
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Relja Popovic
PROVIDER: E-GEOD-57863 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
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.
2014-09-01 | GSE57863 | GEO
Project description:Multiple myeloma (MM) is characterized by recurrent chromosomal translocations. The multiple myeloma SET domain (MMSET), identified by its fusion to the IgH locus in t(4;14) MM, is universally overexpressed and has been suggested to play an important role in tumorigenicity in t(4;14) MM. In order to identify downstream functional targets of MMSET, we knocked down MMSET expression with shRNAs in KMS11, a t(4;14) MM cell line, and identified differentially expressed genes by gene expression microarray analysis.
2014-07-16 | GSE59424 | GEO
Project description:Multiple myeloma (MM) is characterized by recurrent chromosomal translocations. The multiple myeloma SET domain (MMSET), identified by its fusion to the IgH locus in t(4;14) MM, is universally overexpressed and has been suggested to play an important role in tumorigenicity in t(4;14) MM. In order to identify downstream functional targets of MMSET, we knocked down MMSET expression with shRNAs in KMS11, a t(4;14) MM cell line, and identified differentially expressed genes by gene expression microarray analysis. KMS11 cells were treated with shRNAs for 48 h. Total RNA was extracted by using the Qiagen RNeasy Mini kit (Germany). Gene expression was performed using the GeneChip Human Genome U133A Array (Affymetrix) following the manufacturerM-bM-^@M-^Ys instructions. Data analysis was performed using GeneSpring software from Agilent Technologies.
2014-07-16 | E-GEOD-59424 | biostudies-arrayexpress
Project description:The MMSET (Multiple Myeloma SET domain) protein is overexpressed in multiple myeloma patients with the translocation t(4;14). Although studies have shown the involvement of MMSET/WHSC1 in development, its mode of action in the pathogenesis of multiple myeloma (MM) is largely unknown. We found that MMSET is a major regulator of chromatin structure and transcription in t(4;14) MM cells. High levels of MMSET correlate with an increase in lysine 36 methylation of histone H3 and a decrease in lysine 27 methylation across the genome, leading to a more open structural state of the chromatin. Loss of MMSET expression alters adhesion properties, suppresses growth and induces apoptosis in MM cells. Consequently, genes affected by high levels of MMSET are implicated in the p53 pathway, cell cycle regulation and integrin signaling. Regulation of many of these genes required functional histone methyl-transferase (HMT) activity of MMSET. These results implicate MMSET as a major epigenetic regulator in t(4;14)+ MM.
2010-10-20 | GSE24746 | GEO
Project description:The MMSET (Multiple Myeloma SET domain) protein is overexpressed in multiple myeloma patients with the translocation t(4;14). Although studies have shown the involvement of MMSET/WHSC1 in development, its mode of action in the pathogenesis of multiple myeloma (MM) is largely unknown. We found that MMSET is a major regulator of chromatin structure and transcription in t(4;14) MM cells. High levels of MMSET correlate with an increase in lysine 36 methylation of histone H3 and a decrease in lysine 27 methylation across the genome, leading to a more open structural state of the chromatin. Loss of MMSET expression alters adhesion properties, suppresses growth and induces apoptosis in MM cells. Consequently, genes affected by high levels of MMSET are implicated in the p53 pathway, cell cycle regulation and integrin signaling. Regulation of many of these genes required functional histone methyl-transferase (HMT) activity of MMSET. These results implicate MMSET as a major epigenetic regulator in t(4;14)+ MM. Total RNA was isolated from two different systems: an inducible knock down designed in the 5' region of MMSET. Upon addition of doxycycline we block MMSET expression. The second system we used was a repletion system. By retroviral infection of knock out cells for MMSET we restored the expression of MMSET wild type and two mutants of the protein: one active and one catalytically inactive. Triplicates of each sample were analyzed.
2010-10-20 | E-GEOD-24746 | biostudies-arrayexpress
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
2013-08-22 | GSE50072 | GEO
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
Project description:We investigated EZH2 binding in the presence and absence of MMSET protein. MMSET overexpression in t(4;14)+ myeloma leads to global loss of H3K27 methylation and redistribution of EZH2 binding throughout the genome
2014-09-01 | GSE57632 | GEO
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:We investigated EZH2 binding in the presence and absence of MMSET protein. MMSET overexpression in t(4;14)+ myeloma leads to global loss of H3K27 methylation and redistribution of EZH2 binding throughout the genome ChIP-seq for EZH2 in two cell types
2014-09-01 | E-GEOD-57632 | biostudies-arrayexpress