Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Glioblastoma initiating cells are sensitive to histone demethylase inhibition due to loss of DNA repair capacity

ABSTRACT: Cancer stem cells are characterized by their self-renewal properties and their ability to regenerate a tumor. They have chromatin features that are reminiscent of embryonic stem cells. Here, we link these stem cell-like characteristics of human glioblastoma initiating cells (GICs) to a loss of heterochromatin features. Increased histone H3 lysine 9 trimethylation (H3K9me3) levels due to histone demethylase inhibition led to cell death in GICs but not in their differentiated counterparts. The induction of apoptosis was accompanied by the accumulation of DNA double-strand breaks. By ChIP-seq and RNA-seq analysis we found that DNA repair genes of the ATM and ATR pathway lost the active H3 lysine 9 acetylation (H3K9ac) and were downregulated upon knockdown of the histone demethylases KDM4C and KDM7A, while regulators of neuron differentiation were up-regulated. Thus, the H3K9me3-H3K9ac equilibrium is a crucial feature for maintaining the stemness in GICs and represents a chromatin feature that can be exploited to specifically target this tumor subpopulation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE122832 | GEO | 2020/03/02

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Glioblastoma initiating cells are sensitive to histone demethylase inhibition due to epigenetic deregulation

Project description:Tumor-initiating cells are a subpopulation of cells that have self-renewal capacity to regenerate a tumor. Here, we identify stem cell-like chromatin features in human glioblastoma initiating cells (GICs) and link them to a loss of the repressive histone H3 lysine 9 trimethylation (H3K9me3) mark. Increasing H3K9me3 levels by histone demethylase inhibition led to cell death in GICs but not in their differentiated counterparts. The induction of apoptosis was accompanied by a loss of the activating H3 lysine 9 acetylation (H3K9ac) modification and accumulation of DNA damage and downregulation of DDR genes. Upon knockdown of histone demethylases KDM4C and KDM7A both differentiation and DNA damage was induced. Thus, the H3K9me3-H3K9ac equilibrium is crucial for GIC viability and represents a chromatin feature that can be exploited to specifically target this tumor subpopulation.

| EGAS00001003750 | EGA

Gene expresion changes following knockdown of KDM4C in primary fibroblasts

Project description:Epigenetic and genetic regulations are sometimes considered as separate mechanisms that influence gene expression and phenotypes. However, there are DNA sequence variants in epigenetic regulators that could affect gene regulation. The histone demethylase, KDM4C, promotes transcriptional activation by removing the repressive histone mark, tri-methylation of lysine 9 of histone H3 (H3K9me3), from its target genes. In this study, we uncovered cis-acting DNA sequence variants in KDM4C that contribute to individual differences in its expression. Utilizing this natural variation, we performed genetic analyses in B-cells in order to identify target genes that are regulated by KDM4C. We used microarrays to investigate gene expression changes in the target genes from our genetic analyses following knockdown of KDM4C in primary fibroblasts. Primary fibroblasts with stable expression of shRNA targeting KDM4C or a control construct were selected for RNA extraction and hybridization to Affymetrix microarrays. Following selection for stable expression of the shRNA constructs we selected clones expressing 3 non-overlapping constructs targeting KDM4C (shKDM4C) and 2 clones expressing the control construct (shCtr) for analysis by microarray.

2013-09-14 | E-GEOD-41040 | biostudies-arrayexpress

Gene expresion changes following knockdown of KDM4C in primary fibroblasts

2013-09-14 | GSE41040 | GEO

Comparison non-targeting hRNA hESCs versus UBE2K shRNA hESCs

Project description:Histones modulate gene expression by chromatin compaction, regulating numerous processes such as differentiation. However, the mechanisms underlying histone degradation remain elusive. When compared with their differentiated counterparts, immortal human embryonic stem cells (hESCs) have a unique chromatin architecture and low levels of trimethylated histone H3 at lysine 9 (H3K9me3), a heterochromatin-associated modification. Here we assess a link between the intrinsic epigenetic landscape and ubiquitin-proteasome system of hESCs. We find that hESCs exhibit high expression of UBE2K, a ubiquitin-conjugating enzyme. Loss of UBE2K increases the levels of H3K9 trimethyltransferase SETDB1, resulting in H3K9 trimethylation and repression of neurogenic genes during differentiation. Concomitantly, loss of UBE2K impairs the ability of hESCs to differentiate into neural progenitors with neurogenic properties. Besides H3K9 trimethylation, we find that UBE2K binds histone H3 to induce its polyubiquitination and degradation by the proteasome. Notably, ubc-20, the worm orthologue of UBE2K, also regulates both histone H3 levels and H3K9 trimethylation in C. elegans germline. Thus, our results indicate that UBE2K crosses evolutionary boundaries to promote histone H3 degradation and reduce H3K9me3 repressive marks in immortal cells.

2020-06-01 | PXD018625 | Pride

Identification of ubiquitination sites of purified histone H3

2020-06-01 | PXD018621 | Pride

ena-DATASET-DKFZA-04-07-2017-15:50:11:572-96_mod - samples

Project description:Sequence data of 28 Samples (19 chronic lymphocytic leukemia, 9 control) Including RNA-Seq and ChIP-Seq of following histone modifications: H3, H3K4me1, H3K4me3, H3K9ac, H3K9me3, H3K27ac, H3K27me3, H3K36me3 Project see: http://www.cancerepisys.org/

| EGAD00001003421 | EGA

RNA immunoprecipitation (RIP) followed by microarray for identification of miRNA-target genes in human umblical vein endothelial cells (HUVECs).

Project description:Lysine 9 di-methylation and lysine 27 tri-methylation of histone H3 (H3K9me2 and H3K27me3) are mostly linked to gene repression. However, functions of repressive histone methylation dynamics during inflammatory responses remain poorly understood. Here, we show that lysine demethylase 7A (KDM7A) and 6A (UTX) are rapidly transported to nuclear factor kappa-B (NF-κB) related elements in human endothelial cells in response to tumor necrosis factor (TNF)-α. KDM7A and UTX demethylate H3K9me2 and H3K27me3, respectively, and cooperatively activate NF-κB dependent inflammatory genes. Furthermore, using both in situ Hi-C and other 3C based technology, loops between super enhancers (SEs) are newly formed following TNF-α-stimuli at NF-κB-dependent inflammatory loci where KDM7A- and UTX-recruitment coincide. Collectively, these findings suggest that erasing of repressive histone marks by KDM7A and UTX within NF-κB-related elements might functionally associate with formation of SE-SE three-dimensional interactions and could be a cue signal during inflammatory responses in human endothelial cells.

2019-04-11 | GSE121897 | GEO

Genome-wide distribution of histone modification enzymes (KDM7A and UTX), histone modification (H3K9me2, H3K27me3, H3K4me3, H3K27ac), and transcription factor (p65) in TNF-alpha-stimulated human umbilical vein endothelial cell (HUVECs)

2019-04-11 | GSE121890 | GEO

Hi-C analysis in TNF-alpha-stimulated human umblical vein endothelial cells (HUVECs)

2019-04-11 | GSE121520 | GEO

Chromatin Interaction Analysis by Paired-End Tag Sequencing (ChIA-PET) analysis in TNF-alpha-stimulated human umblical vein endothelial cells (HUVECs)

2019-04-11 | GSE121517 | GEO