Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

EC-8042 disrupts both the primary SP/KLF transcription regulatory network and the secondary network induced by HDACi treatment. [SP1&H3K27me3 CUT&Tag]

ABSTRACT: Diffuse intrinsic pontine gliomas (DIPGs), frequently harboring H3K27M mutations, are lethal pediatric brain tumors within no effective treatment. The DIPG-opened chromatin regions are proved to be highly enriched for SP/KLF motifs. Using CUT&Tag of SP1 and H3K27me3 in human pontine progenitor cells (hPPCs) and H3K27M-mutated DIPG cells, we detected the gain of SP1 occupancy correlates with the loss of H3K27me3. Here our epigenomic analyses uncover a marked enrichment of the SP/KLF transcription factors in open chromatin regions specifically in H3K27M-mutated DIPG cells compared to normal pontine neural progenitor cells. We show that SP1 depletion or inhibition of SP/KLF DNA binding with EC-8042, an optimized Mithramycin analog, significantly suppresses the proliferation and invasiveness of H3K27M-DIPG cells. In a screen of epigenetic drugs, we find that histone deacetylase inhibitors (HDACi) synergize with EC-8042 to suppress H3K27M-DIPG cell growth. CUT&Tag of SP1 in SU-DIPG-XVII cells after treated with DMSO, EC-8042, vorinostat and combination vorinostat with EC-8042 revealed that HDACi treatment enhances chromatin accessibility to SP/KLF factors, while EC-8042 disrupts both the primary SP/KLF transcription regulatory network and the secondary network induced by HDACi treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE268110 | GEO | 2025/02/20

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

EC-8042 disrupts both the primary SP/KLF transcription regulatory network and the secondary network induced by HDACi treatment. [ATAC-seq]

Project description:Diffuse intrinsic pontine gliomas (DIPGs), frequently harboring H3K27M mutations, are lethal pediatric brain tumors within no effective treatment. By performing ATAC-seq in human pontine progenitor cells (hPPCs) and H3K27M-mutated DIPG cells, we identified that the DIPG-opened chromatin regions are highly enriched for SP/KLF motifs. We show that SP1 depletion or inhibition of SP/KLF DNA binding with EC-8042, an optimized Mithramycin analog, significantly suppresses the proliferation and invasiveness of H3K27M-DIPG cells. In a screen of epigenetic drugs, we find that histone deacetylase inhibitors (HDACi) synergize with EC-8042 to suppress H3K27M-DIPG cell growth. We then performed ATAC-seq in SU-DIPG-XVII cells after treated with DMSO, EC-8042, vorinostat and combination vorinostat with EC-8042. And discovered that HDACi treatment enhances chromatin accessibility to SP/KLF factors, while EC-8042 disrupts both the primary SP/KLF transcription regulatory network and the secondary network induced by HDACi treatment.

2025-02-20 | GSE268109 | GEO

Inhibition of SP/KLF transcription regulatory network and histone deacetylases acts synergistically against H3K27M-DIPG

Project description:Diffuse intrinsic pontine gliomas (DIPGs), frequently harboring H3K27M mutations, are lethal pediatric brain tumors within no effective treatment. Here our epigenomic analyses uncover a marked enrichment of the SP/KLF transcription factors in open chromatin regions specifically in H3K27M-mutated DIPG cells compared to normal pontine neural progenitor cells. We show that SP1 depletion or inhibition of SP/KLF DNA binding with EC-8042, an optimized Mithramycin analog, significantly suppresses the proliferation and invasiveness of H3K27M-DIPG cells. In a screen of epigenetic drugs, we find that histone deacetylase inhibitors (HDACi) synergize with EC-8042 to suppress H3K27M-DIPG cell growth. The RNA-seq in SU-DIPG-IV and SU-DIPG-XVII cells after treated with DMSO, EC-8042, vorinostat and combination vorinostat with EC-8042 revealed that HDACi activates transcriptional programs that enhance tumor adaptability and invasiveness, an effect counteracted by EC-8042. And EC-8042 in combination with HDACi synergistically represses the expression of cell cycle-associated genes and therefore suppresses H3K27M-DIPG cell proliferation, inhibiting tumor progression in orthotopic xenograft models. Transcriptomic analysis further supports that the combination treatment drives transcriptional programs correlating with favorable prognosis in DIPG patients. Therefore, our regulome profiling in H3K27M-DIPGs has provided mechanistic insights into HDACi resistance and a proof-of-concept for novel targeting therapeutics.

2025-02-20 | GSE255013 | GEO

EC-8042 disrupts both the primary SP/KLF transcription regulatory network and the secondary network induced by HDACi treatment. [H3K27me3 ChIP-seq]

Project description:Diffuse intrinsic pontine gliomas (DIPGs) are lethal pediatric brain tumors with limited therapeutic options. Frequently harboring H3K27M mutations, these tumors are resistant to Histone deacetylase inhibitors (HDACi) in clinical trials for yet unclear reasons. Given this, there is a critical need for exploring the reasons of insufficient clinical manifestations of HDACi and identifying effective combinatorial therapeutic strategy for the treatment of DIPG. To explore the possibility of combining HDACi with EC-8042, an analog of Mithramycin that blocks the DNA binding of SP/KLF factors，We performed ChIP-seq of H3K27me3 in SU-DIPG-XVII cells after treated with DMSO, EC-8042, vorinostat and combination vorinostat with EC-8042. And discovered that EC-8042 reverses the activated transcriptional programs caused by HDACi.

2025-02-20 | GSE268111 | GEO

Variant and cell-context specific H3K27M reprogramming results in distinct enhancer architecture and oncogenic states

Project description:Diffuse intrinsic pontine glioma (DIPG) is a fatal malignancy of the childhood pons characterized by a unique lysine-to-methionine substitution in histone-3 at lysine 27 (H3K27M). We show here that the specific Polycomb targets disrupted by H3K27M and resultant oncogenic state is dependent on both the variant of histone-3 and the cell- context in which the mutation occurs. Through primary DIPG tumor characterization and isogenic expression, we show that the same H3K27M mutation displays distinct modes of oncogenic reprogramming and establishes distinct enhancer architecture depending on whether it occurs in genes encoding H3.3 or H3.1. By comparison to non-malignant pediatric pontine tissue, we create a molecular map for DIPG, identifying and functionally validating both shared and subgroup-specific pathophysiology. Directly comparing the earliest events of H3K27M tumor initiation in putative cells-of-origin demonstrates that DIPG arises only from an oligodendrocyte precursor cell state.

2019-10-03 | GSE126319 | GEO

Heterotypic nucleosomes and PRC2 drive DIPG oncogenesis

Project description:Diffuse intrinsic pontine gliomas (DIPG) are characterized by a heterozygous lysine-to-methionine mutation of histone H3 (H3K27M) that potently reduces Polycomb Repressive Complex 2 (PRC2) methylation of wild-type histone H3K27 (H3K27wt). The role of H3K27M and reduced H3K27wt methylation in DIPG pathogenesis has yet to be determined. Here, we have performed epigenomic profiling of patient-derived H3K27M mutant DIPG cells and demonstrate that H3K27M resides in nucleosomes with H3K27wt acetylation (H3K27ac), and H3K27M-H3K27ac containing nucleosomes co-localize with bromodomain proteins at actively transcribed genes and that PRC2 is excluded from H3K27M occupied regions. With respect to therapeutic implications of these observations, we demonstrate that pharmacologic bromodomain protein inhibition suppresses tumor growth in vivo. In total, our results indicate that H3K27M promotes H3K27ac at the expense of H3K27 methylation, and points to bromodomain protein inhibition as a clinical strategy for treating DIPG.

2017-02-27 | GSE78801 | GEO

Histone H3 K27M mediated Regulation of Cancer Cell Stemness and Differentiation in Diffuse Intrinsic Pontine Glioma (DIPG) [RNA-seq]

Project description:Diffuse intrinsic pontine glioma (DIPG) is a rare pediatric brain tumor with a median survival of 10-15 months. Histone H3 is mutated in 80% of DIPGs, dictating tumor location, onset, and outcome. Therapeutic resistance remains a major obstacle to preventing tumor recurrence and is in part driven by cancer stem cells (CSCs), which exhibit self-renewal properties and tumorigenic potential. In previous studies, we have identified these proliferative and tumorigenic features in aldehyde dehydrogenase positive (ALDH+) CSCs in H3K27M mutant DIPG. We hypothesize that ALDH-mediated cancer stemness and resistance may in part be driven by H3K27M. ALDH1A3 expression was reduced in CRISPR-edited DIPG cells (SU-DIPG-XIII) where the H3K27M mutation had been removed (H3K27M-KO). Furthermore, these gained differentiation characteristics and lost their neurosphere-forming potential. The parental (H3K27M) and H3K27M-KO cells were also subjected to ionizing radiation to identify genes responsible for radioresistance in histone-mutated DIPG radioresistance. Nascent transcriptomes were obtained from these cells using bromouridine labeling and capture followed by sequencing (Bru-seq).

2023-08-30 | GSE211833 | GEO

The H3K36me2 writer-reader dependency in H3K27M-DIPG

Project description:The lysine-to-methionine mutation at residue 27 of histone H3 (H3K27M) is a driving mutation in Diffuse Intrinsic Pontine Glioma (DIPG), a highly aggressive form of pediatric brain tumor with no effective treatment and little chance of survival. H3K27M reshapes the epigenome through a global inhibition of PRC2 catalytic activity, displacement of methylation at lysine 27 of histone H3 (H3K27me2/3), and thus promoting oncogenesis of DIPG. As a consequence, a histone modification H3K36me2, antagonistic to H3K27me2/3, is aberrantly elevated. Here, we investigate the role of H3K36me2 in H3K27M-DIPG by tackling its upstream catalyzing enzymes (writers) and downstream binding factors (readers). We determine that NSD1 and NSD2 are the key writers for H3K36me2. Loss of NSD1/2 in H3K27M-DIPG impedes cellular proliferation in vitro and tumorigenesis in vivo, and disrupts tumor-promoting gene expression programs. Further, we demonstrate that LEDGF and HDGF2 are the main readers that mediate the pro-tumorigenic effects downstream of NSD1/2-H3K36me2. Treatment with a chemically modified peptide mimicking endogenous H3K36me2 dislodges LEDGF/HDGF2 from chromatin and specifically inhibits the proliferation of H3K27M-DIPG. Together, our results indicate a functional pathway of NSD1/2-H3K36me2-LEDGF/HDGF2 as an acquired dependency in H3K27M-DIPG and suggest a possibility to target this pathway for therapeutic interventions.

2021-07-21 | GSE174006 | GEO

Proteomic analysis of chemical and genetic EZH2 inhibition in diffuse intrinsic pontine glioma cell lines

Project description:Diffuse Intrinsic Pontine Glioma (DIPG) is a rare and highly aggressive pediatric tumor. The average survival time after diagnosis is less than one year. Currently, there are no effective treatments. Characteristic of DIPG is a mutation in histone H3 which leads to a substitution of Lysine 27 to Methionine (H3K27M) which deregulates Polycomb Repressive Complex 2 (PRC2), including enzymatic activity of EZH2. Previous studies have shown that inhibition of EZH2 by chemical agents decreases DIPG cell proliferation and inhibits tumor growth in vivo. My thesis project aims to confirm that EZH2 could be a therapeutic target using chemical EZH2 inhibitors, small interfering RNAs and a CRISPR/Cas9 approach in a series of DIPG tumor cell lines and to determine underlying molecular mechanisms of action.

2022-04-01 | PXD017525 | Pride

H2A.Z histone variants facilitate HDACi-dependent removal of H3.3K27M mutant protein in paediatric high-grade glioma cells

Project description:Diffuse intrinsic pontine gliomas (DIPG) are a deadly paediatric brain tumours, non-resectable due to brainstem localisation and diffusive growth. Patients with DIPG have a dismal prognosis of 9-12 months of survival with no effective therapy. Over 80% of DIPGs harbour a mutation in histone 3 (H3.3 or H3.1) resulting in a lysine to methionine substitution (H3K27M). H3K27M causes global epigenetic alterations (a loss of H3K27 trimethylation and an increase in H3K27 acetylation) resulting in aberrant gene expression. To date, no therapeutic strategy exists to suppress the levels of oncogenic H3K27M. We show that pan-HDAC inhibitors (HDACi) lead to the temporary but significant reduction in the H3.33K27M protein (up to 80%) in multiple glioma cell lines expressing the H3.3K27M histone variant, without changes in the H3F3A mRNA expression. The H3.3K27M occupancy at the chromatin is greatly reduced upon HDACi (SB939) treatment, as shown by ChIPseq analysis. H3.3K27M loss is most striking at SB939-upregulated genes suggesting the role in repression of these genes. In addition, genes previously reported as H3K27M-dependent become downregulated in response to SB939 treatment. We discover that the SB939-mediated loss of H3.3K27M is partially blocked by a lysosomal inhibitor, chloroquine. Moreover, the loss of H3.3K27M is facilitated by co-occurrence of H2A.Z, as evidenced by the knock-down of H2A.Z histone isoforms. ChIPseq analysis confirms the occupancy of H3.3K27M and H2A.Z at the same SB939-inducible genes. Altogether, we provide new insight into disease-specific mechanism of HDAC inhibition and demonstrate pharmacological modulation of the oncogenic H3.3K27M protein levels. These findings open a new possibility to directly target the H3.3K27M oncohistone, which may be exploited in future therapies.

2023-10-05 | MSV000093052 | MassIVE

Multiple modes of PRC2 inhibition elicit global chromatin alterations in H3K27M pediatric glioma

Project description:A methionine substitution at lysine 27 on histone H3 variants (H3K27M) characterizes ~80% of diffuse intrinsic pontine gliomas (DIPG) and inhibits PRC2 in a dominant negative fashion. Yet, the mechanisms for this inhibition and abnormal epigenomic landscape have not been resolved. Using quantitative proteomics, we discovered that robust PRC2 inhibition requires levels of H3K27M greatly exceeding those of PRC2, seen in DIPG. While PRC2 inhibition requires interaction with H3K27M, we found this interaction on chromatin is transient with PRC2 largely being released from H3K27M. Unexpectedly, inhibition persisted even after PRC2 dissociated from H3K27M-chromatin suggesting a lasting impact on PRC2. Furthermore, allosterically activated PRC2 is particularly sensitive to K27M leading to a failure to spread H3K27me3 at distinct foci. In turn, levels of Polycomb antagonists such as H3K36me2 are elevated suggesting a more global, downstream effect on the epigenome. Together, these findings reveal the conditions required for H3K27M-mediated PRC2 inhibition and reconcile seemingly paradoxical effects of H3K27M on PRC2 recruitment and activity.

2018-08-31 | GSE118954 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data