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Novel Inhibitors of the Histone-Methyltransferase DOT1L Show Potent Antileukemic Activity in Patient-derived Xenografts (ChIP-seq dataset)

ABSTRACT: using ChIP-seq we examined Chromatin occupancy of the MLL-fusion complex members Menin and DOT1L after treatment with DOT1L methyltransferase inhibitors EPZ5676 and the novel compounds "compound 10" and "compound 11" as well as with the Menin-inhibitor VTP50469 in MOLM13 cells. Furthermore we used ChiP-seq to quantify the loss of H3K79me2 (histone mark deposited by DOT1L) after treatment with the DOT1L inhibitors EPZ5676 and "compound 10" in MOLM13 and RS4,11 cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE149183 | GEO | 2020/06/01

REPOSITORIES: GEO

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Novel Inhibitors of the Histone-Methyltransferase DOT1L Show Potent Antileukemic Activity in Patient-derived Xenografts (RNA-seq dataset)

Project description:Using 3-end RNA-seq followed by digital gene expression analyses we assessed genes that change expression upon treatment with the DOT1L-methyltransferase inhibitors EPZ5676 and the novel drug "compound 10"

2020-06-01 | GSE149184 | GEO

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

DOT1L-mediated Murine Neuronal Differentiation associates with H3K79me2 Accumulation and preserves SOX2-Enhancer Accessibility

Project description:To study whether acute inhibition of DOT1L induces global chromatin states alterations, we profile and compare the transcriptome, chromatin accessibility and epigenome (H3K4me3, H3K4me1, H3K27ac, H3K27me3, H3K36me3, H3K9me3, H3K79me2) of mESC and ES-derived NPC, treated with DMSO or EPZ5676.

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Expression profiling of MDA-MB-231 breast cancer cells treated with DOT1L inhibitors and siDOT1L

Project description:MDA-MB-231 cell line with relatively high DOT1L levels was treated with two potent, selective inhibitors of the DOT1L histone methyl transferase. These compounds can inhibit cells migration and invasion and induce differentiation. Here we provide expression profiling data of cells treated with two DOT1L inhibitors [1] [2], DOT1L siRNA (siDOT1L) or control. MDA-MB-231 cells were treated with 1uM compound [1], 5uM compound [1], 2uM compound [2], 10 uM compound [2] (DOT1L inhibitors) or control (0.1% DMSO) for 14 days, or siDOT1L for 7 days. For each unique condition, 2 biological replicates were generated for expression profiling. Compound [1]: EPZ004777 (in Diagle et al., 2011) Compound [2]: Compound 55 (in Anglin et al., 2012)

2015-02-18 | E-GEOD-56630 | biostudies-arrayexpress

Chromatin state changes induced by targeted degradation of MLL-AF9 are phenocopied by combined DOT1L and MENIN inhibition. [RNA-Seq]

Project description:Using RNA-seq we examined the transcriptional changes following MLL-AF9 degradation in MLL-AF9-HA-FKPB12 transformed murine (BM2222) and human (HCB1) cells. We also examined transcriptional changes in human MLL-AF9-HA-FKBP12 transformed cells (HCB1) and MOLM13 cells in response to DOT1L inhibition, Menin-MLL inhibition, and the combination of DOT1L and Menin-MLL inhibition. Lastly we assessed gene expression in murine neutrophils isolated directly from mice.

2022-03-03 | GSE173574 | GEO

Chromatin state changes induced by targeted degradation of MLL-AF9 are phenocopied by combined DOT1L and MENIN inhibition. [ChIP-Seq]

Project description:Using ChIP-seq we examined the occupancy changes of various histone marks and chromatin-bound proteins following accute MLL-AF9 degradation in MLL-AF9-HA-FKPB12 transformed human (HCB1) cells. We also examined occupancy changes of various chromatin-bound proteins in human MLL-AF9-HA-FKBP12 transformed cells (HCB1) and MOLM13 cells in response to DOT1L inhibition, Menin-MLL inhibition, and the combination of DOT1L and Menin-MLL inhibition.

2022-03-03 | GSE173599 | GEO

RNAsequencing of DOT1L inhibitor EPZ5676 treated ALDH1+ and ALDH1- cell populations

Project description:Global gene expression profiles obtained after treating cells with DOT1L inhibitor, EPZ5676

2022-01-29 | GSE194434 | GEO

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 protects neural stem cells from ER stress

Project description:In order to understand the role of H3K79me2 and DOT1L during CNS development, we analysed neural stem cells after pharmacological inhibition of DOT1L (5 µM SGC0946). To identify target genes of DOT1L in the cortex, we determined the transcriptome of cortical progenitor cells derived from E14.5 NMRI mice after interference with DOT1L activity for three days in vitro (DIV3). Therefore, three independent experiments were performed (ctrl1 – inh1, ctrl2 – inh2, ctrl3 – inh3).

2015-12-31 | E-MTAB-3521 | biostudies-arrayexpress

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

Project description: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.

2018-09-23 | GSE108661 | GEO

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