Gene regulation by the lysine demethylase KDM4A in Drosophila
Ontology highlight
ABSTRACT:
ORGANISM(S): Drosophila melanogaster
PROVIDER: GSE36903 | GEO | 2013/04/01
SECONDARY ACCESSION(S): PRJNA157025
REPOSITORIES: GEO
Similar Datasets
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
Project description:We previously identified an essential role for the H3K9me3 histone demethylase, KDM4A, in maintaining AML cell survival, with genetic depletion by shRNA of KDM4A inducing leukaemic cell death with little effect on normal haematopoiesis. We hypothesised KDM4A inhibition may represent a novel and effective strategy to treat AML. To address this, we provided proof-of-principle for the use of KDM4 inhibitors (KDM4Ai) and fully characterised their functional potential in AML cells and identified the epigenetic mechanisms underpinning the essential role of KDM4A activity in THP-1 cells using both ChIP-seq and RNA-seq, delineating and functionally validating the epigenomic network regulated by KDM4A, showing that selective loss of KDM4A is sufficient to induce apoptosis in a broad spectrum of human AML cells. This detrimental phenotype results from a global accumulation of H3K9me3 and H3K27me3 at KDM4A targeted genomic loci thereby causing down-regulation of a KDM4A-PAF1 controlled transcriptional program essential for leukemogenesis, distinct from that of KDM4C.
2022-12-31 | GSE173995 | GEO
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
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 | GSE119250 | GEO
Project description:The importance of germline-inherited posttranslational histone modification in priming early mammalian development is just emerging1-4. Histone H3 lysine 9 (H3K9) trimethylation is associated with heterochromatin and gene repression during cell-fate change5, while histone H3 lysine 4 (H3K4) trimethylation marks active gene promoters6. Mature oocytes are transcriptionally quiescent and possess remarkably broad domains of H3K4me3 (bdH3K4me3)1, 2. It remains unknown, which factors contribute to the maintenance of the bdH3K4me3 landscape. Lysine-specific demethylase 4A (KDM4A) demethylates H3K9me3 at promoters marked by H3K4me3 in actively transcribing somatic cells7. Here, we report that KDM4A-mediated H3K9me3 demethylation at bdH3K4me3 in oocytes is crucial for normal preimplantation development and zygotic genome activation (ZGA) after fertilization. Loss of KDM4A in oocytes causes extensive and aberrant H3K9me3 spreading at bdH3K4me3, resulting in insufficient transcriptional activation ZGA genes, endogenous retroviral elements and long terminal repeat -initiated chimeric transcripts in 2-cell embryos. The catalytic activity of KDM4A is essential for normal epigenetic reprogramming and preimplantation development. Hence, KDM4A plays a crucial role in preserving maternal epigenome integrity required for proper ZGA and transfer of developmental control to the embryo.
| EGAS00001004220 | EGA
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 | GSE129156 | GEO
Project description:Histone lysine demethylase KDM4A is overexpressed in prostate cancer and plays a crucial role in tumor growth and survival. To understand the mechanisms underlying KDM4A-depedent cell growth and survival, microarray analysis was performed in LNCaP cells transduced with control or KDM4A specific-knockdown construct. The role of KDM4A in prostate carcinogenesis involves activation of E2F1 and androgen receptor transcriptional profiles. LNCaP cells were transduced by lentivirus carrying control pLKO.1 (empty vector) or shKDM4A construct (KDM4A-specific shRNA) for three days, followed by RNA extraction. Affymetrix GeneChip Human Genome U133 Plus 2.0 Arrays were used for microarray analysis.
2016-07-26 | E-GEOD-77928 | biostudies-arrayexpress
Project description:To establish a robust cellular model system for screening genes associated with cell invasion, we over-expressed the oncogenic translocated promoter region (Tpr)-MET proteins in SCC23 cells (SCC23/MET). Using a functional siRNA screen, we identified that the histone demethylase KDM4A played a critical role in the invasive growth and metastasis of SCC mediated by the Oncogenic MET. To investigate the molecular mechanism through which KDM4A inhibit the tumor cell invasion, we knock-down KDM4A in SCC23/MET cell and performed a gene microarray to examine which genes may be regulaged by kDM4A. We generated two stable cell lines. one was infected with virus containing scramble and another infected with virus infected with virus containing KDM4A shRNA. Total RNA were extracted from these two cell lines and subject to microarray.
2013-05-03 | E-GEOD-44238 | biostudies-arrayexpress
Project description:Purpose: ChipSeq allows us to identify binding sites of target proteins of interest in the genome, helping create a global profile for the same. Kdm4a is a H3K9me3 histone demethylase that acts to prevent spurious accumulation of this repressive mark at H3K4me3 positive transcription start sites. To complement transcriptome data from Kdm4a mice, we performed Chip-Seq on 2.5dpc mouse uterus of 8-10 week old littermate control and Kdm4a knockout mice for Kdm4a, H3K9me3 and H3K4me3. This would help us check which of the target genes with changed gene expression was due to the direct change in histone lanscape in absence of Kdm4a.
2017-08-17 | GSE96591 | GEO
Project description:Chromatin modulation provides a key checkpoint for controlling cell cycle regulated gene networks. The replicative canonical histone genes are one such gene family under tight regulation during cell division. These genes are most highly expressed during S phase when histones are needed to chromatinize the new DNA template. While this fact has been known for a while, limited knowledge exists about the specific chromatin regulators controlling their temporal expression during cell cycle. Since histones and their associated mutations are emerging as major players in diseases such as cancer, identifying the chromatin factors modulating their expression is critical. The histone lysine tri-demethylase KDM4A is regulated over cell cycle and plays a direct role in DNA replication timing, site-specific rereplication, and DNA amplifications during S phase. Here, we establish an unappreciated role for the catalytically active KDM4A in directly regulating canonical replicative histone gene networks during cell cycle. Of interest, we further demonstrate that KDM4A interacts with proteins controlling histone expression and RNA processing. Together, this study provides a new function for KDM4A in modulating canonical histone gene expression.
2021-10-27 | GSE154684 | GEO