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DOT1L inhibition with EPZ-5676 in human articular chondrocytes from 5 non-OA hip fracture patients

ABSTRACT: To identify DOT1L targets, associated signaling pathways and networks in chondrocytes, we used genome-wide gene expression microarray analysis in human articular chondrocytes of 5 different donors (without known or documented joint disease) treated with EPZ-5676 or vehicle for 4 days. It is known that DOT1L inhibitors require longer time of treatment in order to show effect and influence the expression of MLL target genes in leukemia cells, but we opted for this relatively short inhibition time to be able to identify early changes induced by DOT1L inhibition.

ORGANISM(S): Homo sapiens

PROVIDER: GSE77916 | GEO | 2017/04/20

SECONDARY ACCESSION(S): PRJNA312193

REPOSITORIES: GEO

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DOT1L inhibition with EPZ-5676 in human articular chondrocytes from 5 non-OA hip fracture patients

Project description:To identify DOT1L targets, associated signaling pathways and networks in chondrocytes, we used genome-wide gene expression microarray analysis in human articular chondrocytes of 5 different donors (without known or documented joint disease) treated with EPZ-5676 or vehicle for 4 days. It is known that DOT1L inhibitors require longer time of treatment in order to show effect and influence the expression of MLL target genes in leukemia cells, but we opted for this relatively short inhibition time to be able to identify early changes induced by DOT1L inhibition. Human articular chondrocytes were obtained from 5 non-OA hip fracture patients. The cells were treated with 3 Î¼M EPZ-5676 or vehicle (DMSO) for 4 days.

2017-04-20 | E-GEOD-77916 | biostudies-arrayexpress

Transcriptome analyses by RNA-seq with NELFE knockdown and EPZ-5676 or HMBA treated HCT116 cells

Project description:These analyses aim to investigate transcriptomic changes induced by NELFE knockdown or DOT1L inhibitor (EPZ-5676, 2 uM, 72 h) or p-TEFb activator (HMBA, 10 mM, 24 h) treatment in HCT116 cells

2023-07-01 | GSE234615 | GEO

MLL1 and MLL fusion proteins play distinct roles in regulating MLLleukemic transcription program [RNA-Seq]

Project description:This study describes the transcriptome profiling of: 1) MM-401, a MLL1 specific inhibitor in MAF9 cells; 2) Comparation of the transcriptone profilings of MM-401,EPZ-5676 (Dot1L inhibitor), MI-2(Menin inhibitor) and iBET(Brd4 inhibitor) in MAF9 leukemia cells.

2016-05-12 | GSE68822 | GEO

A novel Menin-MLL inhibitor induces specific chromatin changes and eradicates disease in models of MLL-rearranged leukemia [RNA-seq]

Project description:Cells carrying MLL-rearrangements are sensitive to treatment with VTP-50469 with IC50 in 20-60 nM. We treated MOLM13 or RS4;11 cells with DMSO (0.33%) or VTP-50469 (100-330nM), followed by digital gene expression analyses of 3'end RNA-seq data. We found that very few genes significantly change expression >2-fold after 2 days of treatment, while after 7-day treatment more genes significantly changed expression >2-fold. The genes that lost expression after VTP-50469 treatment were enriched in MLL-fusion target genes and DOT1L-sensitive genes. Moreover, treatment with both EPZ-5676 and VTP-50469 suppress similar subsets of genes, however VTP-50469 suppress genes faster as compared to EPZ-5676. Treatment of PDX with VTP-50469 suppressed similar gene sets, namely MLL-fusion targets and DOT1L-sensitive genes.

2019-11-06 | GSE127506 | GEO

Homo sapiens

Project description:DOT1L inhibition with EPZ-5676 in human articular chondrocytes from 5 non-OA hip fracture patients

| PRJNA312193 | ENA

Gene expression array of human breast cancer cells MCF7 with DMSO-EPZ- EPZ+E2 and shDOT1L+E2 and ZR-75-1 after treatment with DMSO and EPZ

Project description:Gene expression array of human breast cancer cells MCF7 with DMSO-EPZ- EPZ+E2 and shDOT1L+E2 and ZR-75-1 after treatment with DMSO and EPZ

2019-02-08 | E-MTAB-6893 | biostudies-arrayexpress

Periostin induces early articular cartilage degeneration in developmental dysplasia of the hip

Project description:Developmental dysplasia of the hip (DDH) is one of the significant risk factors for hip osteoarthritis. In order to investigate the factors that induce early articular cartilage degeneration of the hip joints that are exposed to reduced dynamic loads arising from hip dislocation , we created rodent models of hip dislocation by swaddling. Notably, expression of periostin (Postn) was increased in the acetabular articular cartilage of the DDH models; Postn was a candidate gene associated with early articular cartilage degeneration. We showed that early articular cartilage degeneration was suppressed in Postn-/- DDH mice. Furthermore, a microgravity environment induced the expression of Postn in chondrocytes through STAT3 signaling. Postn induced catabolic factors, interleukin-6 and matrix metalloproteinase 3, in articular chondrocytes through integrin-nuclear factor κB signaling. Additionally, interleukin-6 stimulated Postn expression through STAT3 signaling. Thus, Postn plays a critical role in early articular cartilage degeneration associated with hip dislocation.

2022-07-20 | GSE173637 | GEO

RNA-seq of Human neck of femur (NOF) fracture hip and osteoarthritic (OA) cartilage

Project description:This SuperSeries is composed of the SubSeries listed below.

2018-03-03 | GSE111358 | GEO

A novel chemical biology high-content strategy for the identification of novel HMT inhibitors reveals a crosstalk between DOT1L and CARM1

Project description:Epigenetic regulation is a dynamic and reversible process that controls gene expression. Abnormal function results in downregulation or upregulation of pathways leading to diseases, such as cancer. The enzymes that establish and maintain epigenetic marks, such as histone methyltransferases (HMTs), are therapeutic targets as their and, importantly, the epigenetic modifications are reversible. Noteworthy, HMTs, as the other epigenetic enzymes and readers, form together multiprotein complexes that in concert regulate histone marks. To probe the epigenetic protein complexes in a biological system, we developed a reliable chemical biology high-content imaging strategy to screen compound libraries on multiple histone marks inside cells simultaneously. The advantage is double: (1) it identifies directly a drug that is active in cells on a specific histone mark and (2) it reveals the crosstalk between the epigenetic marks. By this approach, we identified that compound 4, a published CARM1 (PRMT4) inhibitor, inhibits both histone mark H3R2me2a (regulated by CARM1) and H3K79me2 (regulated by DOT1L) pointing out a synergistic interaction between the two HMTs. The results obtained by the screening assay were validated by mass spectrometry and other techniques confirming the crosstalk between the two marks and HMTs. Prompted by the interaction between CARM1 and DOT1L we combined compound 4 and DOT1L inhibitor EPZ-5676 resulting in a stronger cell proliferation inhibition and apoptosis, indicating that our approach provides also a novel strategy to identify effective synergistic drug combinations for cancer therapy.

2022-05-19 | PXD022873 | Pride

ChIP-Seq of ERalpha and DOT1L in MCF7 cell before and after EPZ004777 and ICI 182,780 treatment

Project description:ChIP-Seq of ERalpha and DOT1L in MCF7 cell before and after EPZ and ICI treatment

2019-02-08 | E-MTAB-6883 | biostudies-arrayexpress