RNA-seq analysis of human pancreas cell line SU8686 treated with DOT1L inhibitor (SGC0946) or DMSO
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA578266 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10306441_1.fastq.gz | Fastqsanger.gz | |||
| SRR10306441_2.fastq.gz | Fastqsanger.gz | |||
| SRR10306442_1.fastq.gz | Fastqsanger.gz | |||
| SRR10306442_2.fastq.gz | Fastqsanger.gz | |||
| SRR10306443_1.fastq.gz | Fastqsanger.gz |
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Project description:To understand the pathway alteration associated with DOT1L inhibition, we performed RNA-seq analysis of DOT1L inhibitor treated human pancreas cell line SU8686. We reported the changed pathways.
2021-06-23 | GSE139070 | GEO
Project description:Cell lines bearing MLL translocations (MV4-11 and MOLM-13) were treated with a potent, selective inhibitor of the DOT1L histone methyl transferase. Treatment of MLL-rearranged cell lines with the DOT1L inhibitor selectively inhibits H3K79 methylation and blocks expression of leukemogenic genes. Here we provide expression profiling data of cells treated with DOT1L inhibitor or vehicle control. MV4-11 cells were treated with 3 uM EPZ004777 (DOT1L inhibitor) or vehicle control (0.1% DMSO) for 2, 4 and 6 days. MOLM-13 cells were treated with 3 uM EPZ004777 (DOT1L inhibitor) or vehicle control (0.1% DMSO) for 6 days. For each unique conditon, 3 biological replicates were generated for expression profiling.
2011-07-11 | E-GEOD-29828 | biostudies-arrayexpress
Project description:Central to the molecular pathogenesis of MLL leukaemia is the abnormal co-optation of members of transcription complexes including disrupter of telomeric silencing 1-like (DOT1L) and bromodomain containing protein 4 (BRD4). Consequently, targeted therapies against DOT1L and BRD4 are currently being evaluated in clinical trials. However, the mechanisms by which BRD4 and DOT1L regulate leukaemogenic transcription programs remain unclear. Using quantitative proteomics, chemoproteomics and biochemical fractionation we find that native BRD4 and DOT1L exist in largely separate protein complexes. Genetic disruption or small molecule inhibition of BRD4 and DOT1L shows marked synergistic activity against MLL-FP leukaemia cell lines, primary human leukaemia cells and murine leukaemia models. Mechanistically, we find a previously unrecognised functional collaboration between DOT1L and BRD4 that is especially important at highly transcribed genes in close proximity to superenhancers. DOT1L via H3K79me2 facilitates the deposition of histone H4 acetylation, which in turn regulates the binding of BRD4 to chromatin. These data provide novel insights into the regulation of transcription and specify a molecular framework for therapeutic intervention in this poor prognostic disease. ChIPSeq of MV4;11 cell treated with DMSO, I-BET, SGC0946 and combination of I-BET and SGC0946
2016-06-12 | E-GEOD-71776 | biostudies-arrayexpress
Project description:Central to the molecular pathogenesis of MLL leukaemia is the abnormal co-optation of members of transcription complexes including disrupter of telomeric silencing 1-like (DOT1L) and bromodomain containing protein 4 (BRD4). Consequently, targeted therapies against DOT1L and BRD4 are currently being evaluated in clinical trials. However, the mechanisms by which BRD4 and DOT1L regulate leukaemogenic transcription programs remain unclear. Using quantitative proteomics, chemoproteomics and biochemical fractionation we find that native BRD4 and DOT1L exist in largely separate protein complexes. Genetic disruption or small molecule inhibition of BRD4 and DOT1L shows marked synergistic activity against MLL-FP leukaemia cell lines, primary human leukaemia cells and murine leukaemia models. Mechanistically, we find a previously unrecognised functional collaboration between DOT1L and BRD4 that is especially important at highly transcribed genes in close proximity to superenhancers. DOT1L via H3K79me2 facilitates the deposition of histone H4 acetylation, which in turn regulates the binding of BRD4 to chromatin. These data provide novel insights into the regulation of transcription and specify a molecular framework for therapeutic intervention in this poor prognostic disease. RNASeq of MV4;11 cell treated with DMSO, I-BET, SGC0946 and combination of I-BET and SGC0946 in duplicate
2016-06-12 | E-GEOD-71777 | biostudies-arrayexpress
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
Project description:Three independent transcriptional profiling experiments were performed to ascertain how Dot1L affects cell fate change. 1) In a timecoure ("Tc"), reprogramming mouse embryonic fibroblasts were treated with DMSO control or Dot1L inhibitor (Dot1Li -SGC0946) for 2 or 4 days. Surprisingly, despite the enrichment of H3K79me2 on thousands of actively transcribed genes, Dot1L inhibition (Dot1Li) results in few changes in steady state mRNA levels during reprogramming, the majority of which are spuriously upregulated. 2) To determine if Dot1Li increased reprogramming beyond the mesenchymal to epithelial transition (MET) that occurs early in reprogramming when starting from MEFs, reprogramming cells were sorted ("Sort") for surface CDH1 expression, and then treated with Dot1Li or control. Dot1Li increased reprogramming efficiency of both CDH1- and CDH1+ populations to a similar extent and few genes were DE. 3) To assess if Dot1Li increased pluripotency acquisition beyond CDH1 upregulation, CDH1 or empty vector was expressed ("Exp") in reprogramming cells. CDH1 expression did not initiate MET, or enhance reprogramming.
2021-04-30 | GSE160580 | GEO
Project description:The child cancer, neuroblastoma (NB), is characterised by a low incidence of mutations and strong oncogenic embryonal driver signals. Many new targeted epigenetic modifier drugs have failed in human trials as monotherapy. We performed a high‐throughput, combination chromatin‐modifier drug screen against NB cells. We screened 13 drug candidates in 78 unique combinations. We found that the combination of two histone methyltransferase (HMT) inhibitors: GSK343, targeting EZH2, and SGC0946, targeting DOT1L, demonstrated the strongest synergy across 8 NB cell lines, with low normal fibroblast toxicity. High mRNA expression of both EZH2 and DOT1L in NB tumour samples correlated with the poorest patient survival. Combination HMT inhibitor treatment caused activation of ATF4‐mediated endoplasmic reticulum (ER) stress responses. In addition, glutathione and several amino acids were depleted by HMT inhibitor combination on mass spectrometry analysis. The combination of SGC0946 and GSK343 reduced tumour growth in comparison to single agents. Our results support further investigation of HMT inhibitor combinations as a therapeutic approach in NB.
2024-11-13 | GSE281811 | GEO
Project description:Adoptive T cell therapy (ACT) is a promising therapeutic approach for cancer patients. The use of allogeneic T cell grafts will improve its applicability and versatility provided that inherent allogeneic responses are controlled. Through extensive chemical probe screening, we found that inhibiting DOT1L, a histone H3-lysine 79 methyltransferase, alleviated allogeneic T cell responses. DOT1L inhibition with SGC0946 selectively ameliorated low-avidity T cell responses but not high-avidity antitumor T cell responses mediated by the high-affinity T cell receptor or chimeric antigen receptor. The inhibition of DOT1L in T cells prevented the development of graft-versus-host disease while retaining potent antitumor activity in xenogeneic ACT models. These results suggest that DOT1L inhibition may enable the safe and effective use of allogeneic antitumor T cells by suppressing unwanted immunological reactions in ACT.
2018-04-20 | GSE108694 | GEO
Project description:Two independent, scaled, chromatin immunoprecipitation experiments were performed to uncover how Dot1l affects epigenetic modification (1) and RNA polymerase II (RNAPII) (2) localization. Mouse embryonic fibroblasts (MEFs), embryonic stem cells (ESCs), and reprogramming MEFs on day 4 treated with control (DMSO) or Dot1l inhibitor (Dot1li -SGC0946) were profiled. 1) Although ESCs have less global enrichment of H3K79me2 by mass spectrometry than MEFs, H3K79me2 is largely localized on the same shared genes in both cells, yet with reduced levels in pluripotent cells. All degrees of H3K79me (1/2/3) are predominately enriched on the same genes across cell types. Treatment with Dot1li evicts H3K79me1/2/3 from MEF specific, ESC specific, and shared genes with H3K79me2 peaks and enables gain of H3K9ac during reprogramming. 2) To understand how genebody epigenetic modifications affect transcription, RNAPII was analyzed. ESCs have less RNAPII enrichment at the transcriptional start site (TSS), but have similar genebody enrichment as somatic cells indicative of more relative elongation. Dot1li treatment during reprogramming reduces RNAPII at the TSS compared to control.
2022-11-01 | GSE190391 | GEO
Project description:DNA Methyltransferase 3A (DNMT3A) is frequently mutated in various hematopoietic malignancies; however, the underlying oncogenic mechanisms remain elusive. Here, we report that DNMT3A mutational âhotspotâ at Arg882 (DNMT3A-R882H) cooperates with constitutively activated RAS in transforming murine hematopoietic stem/progenitor cells (HSPCs) ex vivo and inducing acute leukemias in vivo. DNMT3A-R882H potentiates aberrant transactivation of âstemnessâ gene expression programs, notably transcription factors Meis1, Hox-A, Mn1 and Mycn. Mechanistically, R882-mutated DNMT3A directly binds to cis-regulatory elements of these genes and induces focal CpG hypomethylation reminiscent of what was seen in human leukemias bearing DNMT3A R882 mutation. Furthermore, DNMT3A-R882H induced DNA hypomethylation facilitates gene enhancer/promoter activation and recruitment of Dot1l-associated transcription elongation machineries. Inactivation of Dot1l represses DNMT3AR882H-mediated stem cell gene dysregulation and acute leukemogenicity. In this dataset, we provided gene expression profiling data for (1) RH-RAS leukemia stem cells (RH-RAS LSCs), (2) LSCs transformed by MLL-AF9, (3) LSCs transformed by NUP98-JARID1A, and (4) Dot1l inhibitor-treated RH-RAS LSCs. Gene expression data were generated using Mouse Genome 430 2.0 Microarray (Affymetrix) for four independently derived RH-RAS LSC lines (termed as LSC RH-RAS #1, #2, #3 and #4), two RH-RAS LSC lines (LSC RH-RAS #1 and # 3) treated with 1 µM SGC0946 (a Dot1l-specific small-molecule inhibitor) for 4 days, one MLL-AF9-transformed progenitor line and three NUP98-JARID1A transformed progenitor lines.
2016-06-23 | E-GEOD-71439 | biostudies-arrayexpress