Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

KMT2D regulates specific programs in heart development via histone H3 lysine 4 dimethylation

ABSTRACT: Histone modifying genes involved in histone H3 lysine 4 (H3K4) methylation are critical for heart development, but the roles of these genes are not well understood. Here, we demonstrate a requirement for the H3K4 methyltransferase KMT2D in cardiac precursors and cardiomyocytes during cardiogenesis. Gene expression analysis revealed upregulation of hypoxia response genes, as well as downregulation of ion transport and cell cycle genes, leading to altered calcium handling and cell cycle defects. We further determined that myocardial Kmt2d deletion led to decreased H3K4me2 at promoters and enhancers. Finally, we identified KMT2D binding regions in cardiomyocytes, of which a subset was associated with decreased gene expression and decreased H3K4me2 in mutant hearts. This subset included genes related to ion transport, hypoxia-reoxygenation and cell cycle regulation, suggesting that KMT2D is important for these processes. Our findings indicate that KMT2D is essential for regulating cardiac gene expression during heart development via H3K4 dimethylation.

ORGANISM(S): Mus musculus

PROVIDER: GSE75151 | GEO | 2016/01/28

SECONDARY ACCESSION(S): PRJNA302646

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

H3K4me2 regulates the recovery of protein biosynthesis and homeostasis from UV-induced DNA damage during development and aging

Project description:DNA damage causes cancer, impairs development and accelerates aging. UV irradiation induces transcription-blocking lesions and defects in transcription-coupled nucleotide excision repair lead to developmental failure and premature aging in humans. Following DNA repair, the homeostatic processes need to be reestablished to ensure development and maintain tissue functionality. Here, we report that in C. elegans removal of the MLL/COMPASS H3K4 methyltransferase exacerbates the developmental growth retardation and accelerates aging, while depletion of the H3K4 demethylase, SPR-5, promotes developmental growth and extends lifespan amid UV-induced damage. We demonstrate that specifically the DDR-induced H3K4me2 is associated with the activation of genes regulating RNA transport, splicing, ribosome biogenesis, and protein homeostasis and regulates the recovery of protein biosynthesis that is essential for survival of UV-induced DNA damage. Our study uncovers a role of H3K4me2 in coordinating the recovery of protein biosynthesis and homeostasis that is required for developmental growth and longevity after DNA damage.

2020-10-13 | PXD015354 | Pride

Loss of Kmt2c or Kmt2d drives brain metastasis via KDM6A-dependent upregulation of MMP3

Project description:Histone lysine methyltransferases KMT2C and KMT2D are among the most commonly mutated genes in the highly metastatic TNBC subtype of breast cancer. However, it is not known if mutations of either of these genes similarly effect epigenomic and transcriptomic landscape or if a specific downstream target might influence metastases. Here, we generated heterogenous Kmt2c or Kmt2d KO murine TNBC cell lines side-by-side and performed in vivo metastases assay in syngeneic immunocompetent mice. Deficiency for either Kmt2c or Kmt2d, both, induced brain metastases from formerly non-metastatic cells. scRNAseq showed activation of pro-inflammatory pathways but conversely also increase of immune checkpoint blocking genes. Interestingly, histone mass spectrometry revealed changes of H3K27 but not the main substrate H3K4. However, ChIPseq for both, H3K4 and H3K27 modifications showed significant changes compared to wildtype cells. Strikingly, genome occupancy of H3K27me3 was reduced while H3K27 demethylase KDM6A was enriched on genomes of KO cells. Integration with gene expression data revealed significant correlations with histone and KDM6A ChIPseq, identifying them as a main driver of Kmt2c or Kmt2d KO-specific gene regulation. Although our datasets revealed more unique than shared signatures, we found Mmp3 being a common target upon Kmt2c or Kmt2d KO. Indeed, downregulation of Mmp3 reversed induction of Kmt2c and Kmt2d KO-dependent brain metastases. Finally, we found that Kdm6a knockdown reduces Mmp3 levels, again, leading to reduction of brain metastases of Kmt2c or Kmt2d KO cells.

2024-05-07 | MSV000094701 | MassIVE

KDM5 inhibition is a novel therapeutic strategy for the treatment of KMT2D mutant lymphomas [2]

Project description:Loss of function mutations within KMT2D are a striking feature of the germinal centre lymphomas, with lesions present in 80% of Follicular Lymphoma (FL) and 30% of Diffuse Large B-cell Lymphoma (DLBCL), resulting in decreased H3K4 methylation and altered gene expression. The KDM5 family normally maintains homeostasis through demethylating H3K4me3/2, thus negatively regulating gene expression. We hypothesised that inhibition of KDM5 may re-establish H3K4 methylation and restore the expression of genes repressed upon loss of KMT2D. Using a selective inhibitor of the KDM5 family we were able to increase H3K4me3 levels in DLBCL cell lines, predominantly at gene promoters, ultimately leading to decreased proliferation and cell death in KMT2D mutant cell lines. This appeared to be driven by an increase in the expression of negative regulators of B cell survival pathways, many of which have previously been described as targets of KMT2D and CREBBP, resulting in diminished BCR signalling. We also observed decreased BCL2 expression in all examined t(14;18) positive cell lines, alongside changes in other BCL2 family members in sensitive cell lines. KDM5 sensitivity was confirmed to be dependent on the presence of KMT2D mutations by generating de novo KMT2D mutant cell lines and correcting naturally mutant cell lines, which displayed greater and lesser sensitivity to KDM5 inhibition respectively. KDM5 inhibition may therefore be an effective therapeutic strategy for ameliorating KMT2D loss of function mutations in malignancies such as germinal centre lymphomas.

2021-06-01 | GSE152642 | GEO

KDM5 inhibition is a novel therapeutic strategy for the treatment of KMT2D mutant lymphomas [1]

2021-06-01 | GSE114492 | GEO

Aberrant downstream mechanisms following loss of KMT2C and KMT2D in Pancreatic Ductal Adenocarcinoma

Project description:Genes encoding the histone H3 lysine 4 (H3K4) methyltransferases KMT2C and KMT2D are subject to deletion and mutation in pancreatic ductal adenocarcinomas (PDAC). We examined the functional and transcriptional consequences of loss of these methyltransferases in patients with PDAC. Patients with low KMT2C and KMT2D expression demonstrated a much-improved outcome compared with those expressing high levels. RNA-seq analysis of KMT2C or KMT2D loss in three cell lines (PANC1, SUIT2 and COLO357) identified 31 and 124 differentially expressed genes respectively, with 19 genes common to both methlytransferases. Gene set enrichment analysis, and correlation with publicly available patient gene expression (GEP) datasets, highlighted significant reductions in pathways relating to cell-cycle and cell growth, where gene expression correlated with KMT2C/D depletion. Furthermore, loss of Kmt2d in three murine cell lines increased sensitivity to the nucleoside analogue 5-fluorouracil (5FU). These experiments support critical, non-redundant, roles for KMT2D and KMT2C in PDAC, where depletion impacts cell-cycle to reduce cell proliferation, enhance response to specific chemotherapy, which may improve patient survival.

2016-07-09 | GSE75327 | GEO

H3K4me2 and gene expression profiling in control and KMT2D KD murine B220 cells

Project description:Define and compare H3K4me2 enrichment in murine B220 cells transduced with empty vector (ct) or KMT2D-shRNA. Compare gene expression by RNAseq in murine B220 cells transduced with empty vector (ct) or KMT2D-shRNA. Using H3K4me1/2 ChIPseq and RNAseq we profiled murine B220 purified cells from tumors transduced with EV (n=3) or KMT2D-shRNA (n=3).

2015-08-28 | E-GEOD-67291 | biostudies-arrayexpress

Analysis of transcriptome changes in Kmt2d deletion in cardiac mesoderm, anterior heart field precursors and cardiomyocytes

Project description:KMT2D is required in the cardiac mesoderm, anterior heart field precursors and cardiomyocytes. Kmt2d deletion in cardiac mesoderm (Mesp1Cre) is embryonic lethal at E10.5 and mutants have hypoplastic hearts; Kmt2d deletion in anterior heart field precursors (Mef2cAHF::Cre) deletion is embryonic lethal at E13.5 and mutants have defects in septation of outflow tract and interventricular septum (IVS); Kmt2d deletion in cardiomyocytes (Tnnt2::Cre) deletion is embryonic lethal at E14.5 and mutants have defects in IVS septation and compact myocardium. The goal of this study is to compare changes in gene expression in these Kmt2d conditional deletion mutants and understand common or distinct pathways dysregulated in absence of KMT2D. Whole genome gene expression analysis was performed on RNA isolated from control and mutant embryonic hearts (or right ventricles and outflow tract for anterior heart field deletion samples). Libraries were prepared using Illumina TruSeq Paired-End Cluster Kit v3, and sequenced with the Illumina HiSeq 2500 system for pair-ended 100 base pairs (PE 100 bp).

2015-11-04 | E-GEOD-74679 | biostudies-arrayexpress

H3K4me2 and gene expression profiling in control and KMT2D KD murine B220 cells

2015-08-28 | GSE67291 | GEO

Identification of KMT2D regulated genes in germinal center B cells

Project description:Somatic mutations of the KMT2D methyltransferase gene represent a common genetic lesion in multiple cancer types. In diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL), these mutations are highly recurrent and occur early during tumorigenesis, suggesting a central role in transformation. Here we show that FL/DLBCL-associated KMT2D mutations impair its enzymatic activity and lead to diminished global H3K4 methylation in germinal center (GC) B cells and DLBCL, consistent with the enrichment of KMT2D binding at enhancer and promoter regions marked by mono- and tri-methylation. Conditional deletion of Kmt2d early during B cell development, but not after initiation of the GC reaction, leads to an increase in GC B cells, whose transcriptional profile is enriched in cell-cycle regulatory and B-cell receptor signaling genes. Consistently, Kmt2d-deficient B cells exhibit proliferative advantage ex vivo. Loss of Kmt2d combined with BCL2 deregulation, mimicking FL/DLBCL pathogenesis, leads to an increased incidence of clonal lymphoproliferations resembling the features of the human tumors. These findings suggest that early KMT2D loss facilitates lymphomagenesis by remodeling the epigenetic landscape of the cancer precursor cells. Eradication of KMT2D-deficient cells may represent a rational therapeutic approach targeting early tumorigenic events.

2015-09-10 | GSE67494 | GEO

Differential H3K4 methylation identifies developmentally poised hematopoietic genes

Project description:We assess the concordance of histone H3 lysine 4 dimethylation (H3K4me2) and trimethylation (H3K4me3) on a genome-wide scale in erythroid development by analyzing pluripotent, multipotential and unipotent cell types. Although H3K4me2 and H3K4me3 are concordant at most genes, multipotential hematopoietic cells have a subset of genes that are differentially methylated (H3K4me2+/me3-). These genes are transcriptionally silent, highly enriched in lineage-specific hematopoietic genes, and uniquely susceptible to differentiation-induced H3K4 demethylation. Self-renewing embryonic stem cells, which restrict H3K4 methylation to genes that contain CpG islands (CGIs), lack H3K4me2+/me3- genes. These data reveal distinct epigenetic regulation of CGI and non-CGI genes during development and indicate an interactive relationship between DNA sequence and differential H3K4 methylation in lineage-specific differentiation. Keywords: comparison of different cell lines

2008-04-29 | GSE11044 | 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