Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

DOT1L inhibition blocks multiple myeloma cell proliferation through suppressing IRF4-MYC signaling

ABSTRACT: Epigenetic alterations play an important role in the pathogenesis in multiple myeloma (MM), but its biological and clinical relevance is not fully understood. Here, we show that DOT1L, which catalyzes methylation of histone H3 lysine 79, is required for the survival of MM cells. Treatment with DOT1L inhibitors induced cell cycle arrest and apoptosis in MM cells, and strongly suppressed cell proliferation in vitro. Chromatin immunoprecipitation-sequencing (ChIP-seq) and microarray analysis revealed that DOT1L inhibition downregulated H3K79 dimethylation (H3K79me2) and expression levels of IRF4-MYC signaling genes in MM cells. Our data suggest that DOT1L may play an essential role in the development of MM, and DOT1L inhibition may provide a new therapy for MM treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE108661 | GEO | 2018/09/23

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Inhibition of DOT1L increases osteoclast fusion and resorption and aggravates bone loss

Project description:Osteoclasts are absorptive cells and play a critical role in homeostatic bone remodeling and pathological bone resorption. Emerging evidence suggests an important role for epigenetic regulation of osteoclastogenesis. In this study, we investigated the role of DOT1L, which regulates gene expression epigenetically by histone H3K79 methylation during osteoclast formation. DOT1L and H3K79me2 levels were upregulated during osteoclast differentiation. Small molecule inhibitor- (EPZ5676 or EPZ004777) or short hairpin RNA-mediated reduction in DOT1L expression promoted osteoclast differentiation and resorption. DOT1L inhibition also increased osteoclast area and accelerated bone mass reduction in a mouse ovariectomy (OVX) model of osteoporosis. DOT1L inhibitors did not alter osteoblast differentiation in vitro and in vivo. Proteomics data, together with bioinformatics analysis, revealed that DOT1L inhibition altered reactive oxygen species (ROS) generation, autophagy activation, and cell fusion-related protein expression. ROS generation increased, and autophagy activation and cell migration ability enhancement were verified subsequently by flow cytometry and transwell migration assays. DOT1L inhibition increased NFATc1 nuclear translocation and NF-κB activation and strengthend osteoclast fusion and expression of resorption-related protein CD9, and MMP9 in osteoclasts derived from RAW264.7. Our findings support a new mechanism of DOT1L-mediated H3K79me2 epigenetic regulation of osteoclast differentiation, implicating DOT1L as a new therapeutic target for osteoclast dysregulation-induced disease.

2018-01-24 | PXD006448 | Pride

RNA-seq analysis of murine KMT2A-MLLT3 with DOT1L overexpressed

Project description:We transduced two individual murine KMT2A-MLLT3 AML samples with DOT1L and three days after sorting for DOT1L+ cells collected for RNA-seq MLL-rearranged leukemias have been previously shown to be dependent on the presence of histone 3 lysine 79 (H3K79) dimethylation on the genomic targets of the fusion, and an inhibitor of the H3K79 methyltransferase DOT1L is in clinical trials for MLL-rearranged leukemia. In order to ask what biologic effects overexpression of DOT1L would have on the H3K79me2 ChIP-Seq profiles and MLL-fusion target gene expression, murine leukemias generated by transplanting MSCV-MLL-AF9-GFP transduced lin- cKit+ Sca1+ bone marrow cells were subjected to overexpression of DOT1L. Cells were sorted into low (low level of DOT1L overexpression), high (high level of DOT1L overexpression) and bulk (entire population) samples, and subjected to H3K79me2 ChIP-Seq (using a drosophila spike in for normalization) and RNA-Seq analysis 3 days after transduction.

2019-07-10 | GSE134035 | GEO

DOT1L Inhibits SIRT1 and SUV39H1-Mediated H3K9 Modification to Maintain Gene Expression (array)

Project description:Methylation of histone 3 on lysine 79 (H3K79) is broadly associated with active gene expression in eukaryotes, and the H3K79 methyltransferase DOT1L is indispensable for specific leukemia subtypes like those with MLL-translocations. We found that suppression of the histone deacetylase SIRT1 rescued MLL-AF9 leukemia cells from their dependence on DOT1L. We show that upon DOT1L inhibition, SIRT1 is required for the acquisition of a repressive chromatin state consistent with facultative heterochromatin around MLL-AF9 target genes in leukemia and other genes possess an H3K79me2(hi), H3K9ac(hi), H3K9me2(low) histone modification profile in normal hematopoietic stem and progenitor cells. Examination of gene expression dynamics with and without drug treatment and RNA interference.

2015-03-30 | E-GEOD-61013 | biostudies-arrayexpress

DOT1L Inhibits SIRT1 and SUV39H1-Mediated H3K9 Modification to Maintain Gene Expression (ATACseq)

Project description:Methylation of histone 3 on lysine 79 (H3K79) is broadly associated with active gene expression in eukaryotes, and the H3K79 methyltransferase DOT1L is indispensable for specific leukemia subtypes like those with MLL-translocations. We found that suppression of the histone deacetylase SIRT1 rescued MLL-AF9 leukemia cells from their dependence on DOT1L. We show that upon DOT1L inhibition, SIRT1 is required for the acquisition of a repressive chromatin state consistent with facultative heterochromatin around MLL-AF9 target genes in leukemia and other genes possess an H3K79me2(hi), H3K9ac(hi), H3K9me2(low) histone modification profile in normal hematopoietic stem and progenitor cells. Examination of histone modifications and a chromatin modifier with and without drug treatment and RNA interference.

2015-03-30 | E-GEOD-61016 | biostudies-arrayexpress

DOT1L Inhibits SIRT1 and SUV39H1-Mediated H3K9 Modification to Maintain Gene Expression (ChIPseq)

Project description:Methylation of histone 3 on lysine 79 (H3K79) is broadly associated with active gene expression in eukaryotes, and the H3K79 methyltransferase DOT1L is indispensable for specific leukemia subtypes like those with MLL-translocations. We found that suppression of the histone deacetylase SIRT1 rescued MLL-AF9 leukemia cells from their dependence on DOT1L. We show that upon DOT1L inhibition, SIRT1 is required for the acquisition of a repressive chromatin state consistent with facultative heterochromatin around MLL-AF9 target genes in leukemia and other genes possess an H3K79me2(hi), H3K9ac(hi), H3K9me2(low) histone modification profile in normal hematopoietic stem and progenitor cells. Examination of histone modifications and a chromatin modifier with and without drug treatment and RNA interference.

2015-03-30 | E-GEOD-61021 | biostudies-arrayexpress

Global gene expression analysis of Dot1l-deficient and control intestinal villus cells in mouse

Project description:Methylation of H3K79 is associated with chromatin at expressed genes, though it is unclear if this histone modification is required for transcription of all genes. Recent studies suggest that Wnt-responsive genes depend particularly on H3K79 methylation, which is catalyzed by the methyltransferase DOT1L. Human leukemias carrying MLL gene rearrangements show DOT1L-mediated H3K79 methylation and aberrant expression of leukemogenic genes. DOT1L inhibitors reverse these effects but their clinical use is potentially limited by toxicity in Wnt-dependent tissues such as intestinal epithelium. Genome-wide positioning of the H3K79me2 mark in Lgr5+ mouse intestinal stem cells and mature intestinal villus epithelium correlated with mRNA expression levels but not with Wnt-responsive genes per se. Selective Dot1l disruption in Lgr5+ stem cells or in all intestinal epithelial cells eliminated H3K79me2 from the respective compartments, allowing genetic evaluation of DOT1L requirements. Absence of methylated H3K79 did not impair health, intestinal homeostasis or expression of Wnt target genes in crypt epithelium for up to 4 months, despite increased crypt cell apoptosis. Global transcript profiles in Dot1l-null cells were barely altered. Thus, H3K79 methylation is not essential for transcription of Wnt-responsive or other intestinal genes and intestinal toxicity is not imperative when DOT1L is rendered inactive in vivo. Examination of differential gene expression between Dot1l control (Dot1 f/f) and Dot1l mutant (Villin-Cre, Dot1l f/f) villus cells.

2012-10-19 | E-GEOD-41710 | biostudies-arrayexpress

DOT1L Inhibits SIRT1 and SUV39H1-Mediated H3K9 Modification to Maintain Gene Expression [ChIP-seq 2]

Project description:Methylation of histone 3 on lysine 79 (H3K79) is broadly associated with active gene expression in eukaryotes, and the H3K79 methyltransferase DOT1L is indispensable for specific leukemia subtypes like those with MLL-translocations. We found that suppression of the histone deacetylase SIRT1 rescued MLL-AF9 leukemia cells from their dependence on DOT1L. We show that upon DOT1L inhibition, SIRT1 is required for the acquisition of a repressive chromatin state consistent with facultative heterochromatin around MLL-AF9 target genes in leukemia and other genes possess an H3K79me2(hi), H3K9ac(hi), H3K9me2(low) histone modification profile in normal hematopoietic stem and progenitor cells. Examination of histone modifications via ChIP-seq in three human cancer cell lines.

2015-03-30 | E-GEOD-62100 | biostudies-arrayexpress

DOT1L Inhibits SIRT1 and SUV39H1-Mediated H3K9 Modification to Maintain Gene Expression (ATACseq)

2015-03-30 | GSE61016 | GEO

DOT1L Inhibits SIRT1 and SUV39H1-Mediated H3K9 Modification to Maintain Gene Expression (ChIPseq)

2015-03-30 | GSE61021 | GEO

DOT1L Inhibits SIRT1 and SUV39H1-Mediated H3K9 Modification to Maintain Gene Expression (array)

2015-03-30 | GSE61013 | GEO