Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Elongin B orchestrates chromatin and transcriptional programs in H3K27M‑mutant diffuse midline glioma [XIII_ELOBKO_RNAseq]

ABSTRACT: Recurrent driver mutations in genes encoding histone H3 (H3.3K27M and H3.1K27M) are observed in ~80% of diffuse midline gliomas (DMG), which lead to aberrant gene regulation, yet the specific RNA polymerase 2 (Pol2) regulators inducing aberrant DMG transcription are not fully defined. We identified multiple regulators of Pol2 elongation as DMG genetic dependencies in a chromatin-focused CRISPR screen. Additional studies confirm that knockout (KO) of the Pol2 SIII complex gene Elongin B (ELOB) inhibits DMG cell proliferation in tissue culture and tumor growth in xenograft models. Further genomic analyses reveal that ELOB binding sites are enriched in H3K27M oncohistones and that ELOB knockout alters H3K27me3 and H3K27M incorporation at thousands of genomic regions, suggesting a role for ELOB in maintaining dysfunctional chromatin states in DMG. Correspondingly, ELOB loss disrupts Pol2 transcriptional activity and alters the expression of transcripts involved in metabolism, proliferation, and brain development. These findings suggest that Pol2 elongation factors cooperate with H3K27M oncohistones to maintain the epigenetic and transcriptional landscape driving DMG malignancy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE324874 | GEO | 2026/04/27

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Elongin B orchestrates chromatin and transcriptional programs in H3K27M‑mutant diffuse midline glioma [XIII_K27MKO_CUTandRUN]

Project description:Recurrent driver mutations in genes encoding histone H3 (H3.3K27M and H3.1K27M) are observed in ~80% of diffuse midline gliomas (DMG), which lead to aberrant gene regulation, yet the specific RNA polymerase 2 (Pol2) regulators inducing aberrant DMG transcription are not fully defined. We identified multiple regulators of Pol2 elongation as DMG genetic dependencies in a chromatin-focused CRISPR screen. Additional studies confirm that knockout (KO) of the Pol2 SIII complex gene Elongin B (ELOB) inhibits DMG cell proliferation in tissue culture and tumor growth in xenograft models. Further genomic analyses reveal that ELOB binding sites are enriched in H3K27M oncohistones and that ELOB knockout alters H3K27me3 and H3K27M incorporation at thousands of genomic regions, suggesting a role for ELOB in maintaining dysfunctional chromatin states in DMG. Correspondingly, ELOB loss disrupts Pol2 transcriptional activity and alters the expression of transcripts involved in metabolism, proliferation, and brain development. These findings suggest that Pol2 elongation factors cooperate with H3K27M oncohistones to maintain the epigenetic and transcriptional landscape driving DMG malignancy.

2026-04-27 | GSE324873 | GEO

Elongin B orchestrates chromatin and transcriptional programs in H3K27M‑mutant diffuse midline glioma [XIII_ELOB_CUTandRUN]

2026-04-27 | GSE324878 | GEO

Elongin B orchestrates chromatin and transcriptional programs in H3K27M‑mutant diffuse midline glioma [XIII_ELOBKO_chIP_ELOB_RNAPII]

2026-04-27 | GSE324875 | GEO

H3.1K27M-induced misregulation of the TSK/TONSL-H3.1 pathway causes genomic instability

Project description:The oncomutation lysine 27-to-methionine in histone H3 (H3K27M) is frequently identified in tumors of patients with diffuse midline glioma-H3K27 altered (DMG-H3K27a). H3K27M inhibits the deposition of the histone mark H3K27me3, which affects the maintenance of transcriptional programs and cell identity. Cells expressing H3K27M are also characterized by defects in genome integrity, but the mechanisms linking expression of the oncohistone to DNA damage remain mostly unknown. In this study, we demonstrate that expression of H3.1K27M in the model plant Arabidopsis thaliana interferes with post-replicative chromatin maturation mediated by the H3.1K27 methyltransferases ATXR5 and ATXR6. As a result, H3.1 variants on nascent chromatin remain unmethylated at K27 (H3.1K27me0), leading to ectopic activity of TONSOKU (TSK), which induces DNA damage and genomic alterations. Elimination of TSK activity suppresses the genome stability defects associated with H3.1K27M expression, while inactivation of specific DNA repair pathways prevents survival of H3.1K27M-expressing plants. Overall, our results suggest that H3.1K27M disrupts the chromatin-based mechanisms regulating TSK/TONSL activity, which causes genomic instability and may contribute to the etiology of DMG-H3K27a.

2025-04-01 | MSV000097474 | MassIVE

CHD2 Regulates Neuron-glioma Interactions in Pediatric Glioma

Project description:High-grade gliomas (HGG) are deadly diseases for both adult and pediatric patients. Recently, it has been shown that neuronal activity promotes the progression of multiple subgroups of HGG. However, epigenetic mechanisms that govern this process remain elusive. Here we report that the chromatin remodeler CHD2 regulates neuron-glioma interactions in diffuse midline glioma (DMG) characterized by onco-histone H3.1K27M. Depletion of CHD2 in H3.1K27M DMG cells compromises cell viability and neuron-to-glioma synaptic connections in vitro, neuron-induced proliferation of H3.1K27M HGG DMG cells in vitro and in vivo, activity-dependent calcium transients in vivo, and extends the survival of H3.1K27M DMG-bearing mice. Mechanistically, CHD2 coordinates with the transcription factor FOSL1 to control the expression of axon-guidance and synaptic genes in H3.1K27M DMG cells. Together, our study reveals a mechanism whereby CHD2 controls the intrinsic gene program of the H3.1K27M DMG subtype, which in turn regulates the tumor growth-promoting interactions of glioma cells with neurons.

2024-05-09 | GSE211074 | GEO

Human diffuse intrinsic pontine glioma (DIPG) LC-MSMS

Project description:Diffuse intrinsic pontine glioma (DIPG), a lethal pediatric cancer driven by H3K27M oncohistones, exhibits aberrant epigenetic regulation and stem-like cell states. Here, we uncover an axis involving H3.3K27M oncohistones, CREB5/ID1, which sustains the stem-like state of DIPG cells, promoting malignancy. We demonstrate that CREB5 mediates elevated ID1 levels in the H3.3K27M/ACVR1WT subtype, promoting tumor growth; while BMP signaling regulates this process in the H3.1K27M/ACVR1MUT subtype. Furthermore, we reveal that H3.3K27M directly enhances CREB5 expression by reshaping the H3K27me3 landscape at the CREB5 locus, particularly at super-enhancer regions. Additionally, we elucidate the collaboration between CREB5 and BRG1, the SWI/SNF chromatin remodeling complex catalytic subunit, in driving oncogenic transcriptional changes in H3.3K27M DIPG. Intriguingly, disrupting CREB5 super-enhancers with ABBV-075 significantly reduces its expression and inhibits H3.3K27M DIPG tumor growth. Combined treatment with ABBV-075 and a BRG1 inhibitor presents a promising therapeutic strategy for clinical translation in H3.3K27M DIPG treatment.

2025-01-28 | PXD060271 | Pride

Human diffuse intrinsic pontine glioma (DIPG) LC-MSMS

2025-01-28 | PXD053094 | Pride

Multi-omics approaches reveal that Diffuse Midline Gliomas are susceptible to replication stress therapy and cholesterol biosynthesis inhibition [RNA-seq]

Project description:The fatal Diffuse Midline Gliomas (DMG) are characterized by an undruggable H3K27M mutation in H3.1 or H3.3. K27M impairs normal development by stalling of differentiation. As replication timing influences gene expression, cell fate, and cellular response to therapeutics, we undertook a multi-omics approach (Repli-seq, cell cycle RNA-seq, single cell RNA-seq) in DMG cells (H3.1K27M and H3.3K27M subgroups) and tumors in comparison to normal brain to gain an appreciation for targetable pathways in DMG. DMG cells presented differential replication timing in each subgroup, which, in turn, correlated with significant differential gene expression including the cholesterol biosynthesis pathway. Consistent with these findings, DMG tumors presented high replication stress and cholesterol biosynthesis pathway signatures. Moreover, DMG cells were specifically vulnerable to an inhibitor of the cholesterol pathway and to a replication stress therapy, singly and in combination. In conclusion, this combinatorial genomics approach revealed insights into therapeutic opportunities for this incurable disease.

2024-11-20 | GSE268776 | GEO

Multi-omics approaches reveal that Diffuse Midline Gliomas are susceptible to replication stress therapy and cholesterol biosynthesis inhibition [Repli-seq]

2024-11-20 | GSE268775 | GEO

Peptide-mediated inhibition of the transcriptional regulator Elongin BC induces apoptosis in cancer cells

Project description:Inhibiting protein-protein interactions via designed peptides is a suitable strategy to block the function of important proteins in cells. The Elongin BC heterodimer (ELOB/C) is involved in transcription elongation and protein turnover. It interacts with target proteins via a so-called BC-box to modulate their functions. ELOB and ELOC are commonly upregulated in cancer and are essential for cancer cell growth, making them attractive drug targets. However, currently, no strategy has been established to inhibit the function of ELOB/C in cells. Here, we show that peptides that mimic the high-affinity BC-box of EPOP can block the interaction of ELOB/C with its target proteins, both in vitro and in the cellular environment. Cancer cells treated with BC-box peptides, but not with the mutated control, show decreased cell viability, altered cell cycle and increased apoptosis, demonstrating a biological impact by inhibiting ELOB/C in vivo. Together our work suggests that targeting the BC-box binding pocket of ELOB/C is a feasible strategy to impair the function of the ELOB/C heterodimer and to inhibit cancer cell growth.

2023-06-27 | PXD038414 | Pride

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