Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Expression landscape of human stromal cells in preclinical trials involving chemotherapeutic and histone demethylase KDM4-targeting agents

ABSTRACT: Aging and age-related pathologies including multiple cancer types can be controlled by specifically targeting senescent cells, or more specifically, their hallmark feature, the senescence-associated secretory phenotype (SASP). Lysine methylation is one of the most common histone posttranslational modifications that regulate chromatin structure in mammalian cells. Changes in histone lysine methylation status have been observed during cancer progression, a consequence of dysregulation of histone lysine methyltransferases and/or their opposing demethylases. KDM4 (or JMJD2) encompasses demethylases that target histone H3 on lysines 9 and 36 sites. Frequently overexpressed in breast, colorectal, lung, prostate, and other tumor types and required for efficient cancer cell proliferation, KDM4 proteins represent novel drug targets. However, emerging studies are beginning to uncover the functional roles of KDM4 in epigenomic regulation during cellular senescence and organismal aging, thus providing a new angle to understand human aging and allowing expansion of the existing list of epigenetic targets, the drugs of which are currently limited to the pharmacological arsenal against DNA methyltransferases and histone deacetylases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE160091 | GEO | 2021/03/23

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

RNA-seq using RNA from KDM4 WT and Knockout haematopoietic stem cells

Project description:The KDM4/JMJD2 are H3K9- and H3K36- specific demethylases, which are considered promising therapeutic targets for the treatment of acute myeloid leukemia (AML) harboring MLL-translocations. Here, we investigate the long-term effects of depleting KDM4 activity on normal hematopoiesis to probe potential side effects of continuous inhibition of these enzymes. Utilizing conditional Kdm4a/Kdm4b/Kdm4c triple-knockout mice we show that KDM4 activity is required for hematopoietic stem cell (HSC) maintenance in vivo. The knockout of the KDM4 demethylases leads to accumulation of H3K9me3 on transcription start sites and the corresponding downregulation of expression of several genes in hematopoietic stem cells. We show that two of these genes, Taf1b and Nom1, are essential for the maintenance of hematopoietic cells. Taken together, our results show that the KDM4 demethylases are required for the expression of genes essential for the long-term maintenance of normal hematopoiesis.

2019-04-02 | GSE129137 | GEO

The KDM4/JMJD2 histone demethylases are required for hematopoietic stem cell maintenance

Project description:The KDM4/JMJD2 histone demethylases are required for hematopoietic stem cell maintenance

| PRJNA530243 | ENA

KDM4 inhibition targets breast cancer stem cells

Project description:Cancer progression is associated with alterations of epigenetic regulators such as histone-lysine demethylases 4 (KDM4)2-5. During breast cancer therapy, classical treatments fail to address resistant cancer stem cell populations6-10. Here, we identified a novel KDM4 inhibitor (KDM4(i)) with unique preclinical characteristics. KDM4(i) is a highly potent pan KDM4 inhibitor that specifically blocks the demethylase activity of KDM4A, B, C, and D but not that of the other members of the KDM family. We validated the KDM4(i) anti-tumoral properties under conditions recapitulating patient tumors. Therefore, we established a method to isolate and grow triple-negative breast cancer stem cells (BCSCs) from individual patient tumors after neoadjuvant chemotherapy. Limiting dilution orthotopic xenografts of these BCSCs faithfully regenerate original patient tumor histology and gene expression. KDM4(i) blocks proliferation, sphere formation and xenograft tumor growth of BCSCs. Importantly, KDM4(i) abrogates expression of EGFR, a driver of therapy-resistant triple-negative breast tumor cells11, via inhibition of the KDM4A demethylase activity. Taken together, we present a unique BCSC culture system as a basis for therapeutic compound identification and demonstrate that KDM4 inhibition is a new therapeutic strategy for the treatment of triple-negative breast cancer.

2018-04-10 | GSE95042 | GEO

Jmjd2a and Jmjd2c regulate H3K9me3 and H3K36me3 at H3K4me3 positive transcription start sites being essential for ESC self-renewal and embryogenesis (ChIP-Seq)

Project description:We have characterized the role of the Jmjd2/Kdm4 proteins in embryonic stem cell (ESC) biology, histone methylation and gene regulation. The Jmjd2 proteins are H3K9/H3K36 histone demethylases and three Jmjd2 family members are expressed in ESCs: Jmjd2a/Kdm4a, Jmjd2b/Kdm4b and Jmjd2c/Kdm4c/Gasc1. We find that specifically Jmjd2a and Jmjd2c exert redundant functions, which are essential for ESC self-renewal and early embryonic development. ChIP-seq studies show that Jmjd2a and Jmjd2c both localize to H3K4me3 marked regions, where they have general and widespread roles preventing the accumulation of especially H3K9me3, but also H3K36me3. Jmjd2 catalytic activity is required for ESC maintenance, and increased H3K9me3 levels in knockout ESCs compromise the expression of several Jmjd2a/c targets, including genes that are important for ESC self-renewal. Thus, continual removal of H3K9 promoter methylation by Jmjd2 demethylases represents a novel mechanism ensuring transcriptional competence and stability of the pluripotent cell identity.

2016-05-09 | GSE64252 | GEO

Jmjd2a and Jmjd2c regulate H3K9me3 and H3K36me3 at H3K4me3 positive TSSs being essential for ESC self-renewal and embryogenesis (microarray)

2016-05-09 | GSE64251 | GEO

Genome-wide maps of H3K9me3 in hematopoietic stem cells from Kdm4a, b, c triple knockout mice

2019-04-02 | GSE129156 | GEO

H3K14me3 Genomic Distributions and its regulation by KDM4 family demethylases [Mm]

Project description:Histone lysine methylations are essential components of the epigenetic regulatory mechanisms. Although major histone lysine methylations have been extensively investigated, low-abundance methylations remain largely under-studied. Among the low-abundance methylations, H3K14me3 has been identified in mammalian cells upon pathological infection by Legionella pneumophila, a gram-negative bacterium and causative agent of a severe form of pneumonia. Global host chromatin H3K14 trimethylation and transcription repression are mediated by an H3K14 methyltransferase, regulator of methylation A (RomA) encoded by the bacterial genome 1. Importantly, previous mass spectrometry studies also suggested the presence of endogenous H3K14 methylations among eukaryotes 2-7, although these findings have not been confirmed by independent means. In addition, the genomic distribution as well as the H3K14me3 regulatory enzymes have not been identified. Here, using an H3K14me3-specific antiserum we report the identification of distinct and shared H3K14me3 distribution patterns in HEK293T and human embryonic stem cells (hESCs), two cell lines with extensive epigenome profiles allowing cross comparisons with other known histone marks. H3K14me3 heavily decorates the KRAB-ZNF (Krupple-associated box containing zinc finger gene) clusters in both the HEK293T and hESC cells but is only strongly associated with active transcription in HEK293T cells, where it binds thousands of active promoters. We further profiled H3K14me3 in a mouse melanoma cell line, B16, and discovered similar distribution features as those in HEK293T cells. Importantly, we identified members of the KDM4 family of histone demethylases (KDM4A, KDM4B and KDM4C) as H3K14me3 demethylases. As the KDM4 family members have been shown to mediate H3K9me3 and H3K36me3 demethylation 8, our findings also revealed crosstalks among these modifications.

2018-12-31 | GSE119251 | GEO

H3K14me3 Genomic Distributions and its regulation by KDM4 family demethylases [Hs]

2018-12-31 | GSE119250 | GEO

Gene regulation by the lysine demethylase KDM4A in Drosophila

Project description:Lysine methylation of histones is associated with both transcriptionally active chromatin and with silent chromatin, depending on what residue is modified. Histone methyltransferases and demethylases ensure that histone methylations are dynamic and can vary depending on cell cycle- or developmental stage. KDM4A demethylates H3K36me3, a modification enriched in the 3’end of active genes. The genomic targets and the role of KDM4 proteins in development remain largely unknown. To investigate the link between dKDM4A and transcription, and to unravel molecular targets on a genome-wide scale, we used microarrays to decipher gene expression changes in dKDM4A mutant 1st instar larvae and identified classes of up-regulated and down-regulated genes. Three replicates of 200 dKDM4A KG04636 / ∆dKDM4A and dKDM4A precise KG06436 / dKDM4A precise NP0618 Drosophila 1st instar larvae for RNA extraction and hybridization on Affymetrix microarrays.

2013-04-01 | E-GEOD-36903 | biostudies-arrayexpress

Gene regulation by the lysine demethylase KDM4A in Drosophila

2013-04-01 | GSE36903 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

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