Inhibition of Jumonji demethylases transcriptionally reprograms severe cardiac hypertrophy and prolongs survival
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ABSTRACT:
PROVIDER: PRJNA714236 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
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| SRR13958612_1.fastq.gz | Fastqsanger.gz | |||
| SRR13958612_2.fastq.gz | Fastqsanger.gz | |||
| SRR13958613_1.fastq.gz | Fastqsanger.gz | |||
| SRR13958613_2.fastq.gz | Fastqsanger.gz | |||
| SRR13958614_1.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:Inhibition of Jumonji demethylases transcriptionally reprograms severe cardiac hypertrophy and prolongs survival.
| PRJNA733239 | ENA
Project description:Cardiac hypertrophy is a potentially fatal disease characterized by increased cardiomyocyte size, and maladaptive transcriptional remodeling that leads to arrythmias and contractile failure. Transgenic mice constitutively expressing high levels of calcineurin develop extreme heart hypertrophy and generally die within a few weeks of birth. Here, we characterize the transcriptional and epigenetic pathways that are aberrant in this mouse model and establish a pharmacological approach to treating cardiac hypertrophy based on our observation that a subset of histone demethylases of the Jumonji KDM family that act on H3K4me3 or H3K9me3 are markedly increased at the protein level and show enhanced enzymatic activity in diseased hearts. Inhibition of Jumonji demethylases in vivo results in lower histone demethylase enzymatic activity in the heart without toxicity, and leads to partial reduction of heart size, to the reversal of maladaptive transcriptional programs, to improved heart function, and to prolongation of survival. Mechanistically, MEF2, KDM4A and KDM3A target genes are specifically regulated in response to pharmacological or genetic inhibition of Jumonji demethylases and NFAT remains largely cytoplasmic. Similar transcriptional reversal of disease genes is seen in a second disease model based on cardiac mechanical overload, suggesting the generality of this approach. Our findings establish the use of pharmacological inhibitors of Jumonji enzymes as potential therapeutics for the treatment of cardiac hypertrophy across disease models and provides evidence of the reversal of maladaptive transcriptional reprogramming in the heart leading to partial restoration of cardiac function.
2022-02-08 | GSE175711 | GEO
Project description:Cardiac hypertrophy is a potentially fatal disease characterized by increased cardiomyocyte size, and maladaptive transcriptional remodeling that leads to arrythmias and contractile failure. Transgenic mice constitutively expressing high levels of calcineurin develop extreme heart hypertrophy and generally die within a few weeks of birth. Here, we characterize the transcriptional and epigenetic pathways that are aberrant in this mouse model and establish a pharmacological approach to treating cardiac hypertrophy based on our observation that a subset of histone demethylases of the Jumonji KDM family that act on H3K4me3 or H3K9me3 are markedly increased at the protein level and show enhanced enzymatic activity in diseased hearts. Inhibition of Jumonji demethylases in vivo results in lower histone demethylase enzymatic activity in the heart without toxicity, and leads to partial reduction of heart size, to the reversal of maladaptive transcriptional programs, to improved heart function, and to prolongation of survival. Mechanistically, MEF2, KDM4A and KDM3A target genes are specifically regulated in response to pharmacological or genetic inhibition of Jumonji demethylases and NFAT remains largely cytoplasmic. Similar transcriptional reversal of disease genes is seen in a second disease model based on cardiac mechanical overload, suggesting the generality of this approach. Our findings establish the use of pharmacological inhibitors of Jumonji enzymes as potential therapeutics for the treatment of cardiac hypertrophy across disease models and provides evidence of the reversal of maladaptive transcriptional reprogramming in the heart leading to partial restoration of cardiac function.
2022-02-08 | GSE168847 | GEO
Project description:Inhibition of Jumonji demethylases transcriptionally reprograms severe cardiac hypertrophy and prolongs survival: part 2.
| PRJNA715174 | ENA
Project description:Cardiac hypertrophy is a potentially fatal disease characterized by increased cardiomyocyte size, and maladaptive transcriptional remodeling that leads to arrythmias and contractile failure. Transgenic mice constitutively expressing high levels of calcineurin develop extreme heart hypertrophy and generally die within a few weeks of birth. Here, we characterize the transcriptional and epigenetic pathways that are aberrant in this mouse model and establish a pharmacological approach to treating cardiac hypertrophy based on our observation that a subset of histone demethylases of the Jumonji KDM family that act on H3K4me3 or H3K9me3 are markedly increased at the protein level and show enhanced enzymatic activity in diseased hearts. Inhibition of Jumonji demethylases in vivo results in lower histone demethylase enzymatic activity in the heart without toxicity, and leads to partial reduction of heart size, to the reversal of maladaptive transcriptional programs, to improved heart function, and to prolongation of survival. Mechanistically, MEF2, KDM4A and KDM3A target genes are specifically regulated in response to pharmacological or genetic inhibition of Jumonji demethylases and NFAT remains largely cytoplasmic. Similar transcriptional reversal of disease genes is seen in a second disease model based on cardiac mechanical overload, suggesting the generality of this approach. Our findings establish the use of pharmacological inhibitors of Jumonji enzymes as potential therapeutics for the treatment of cardiac hypertrophy across disease models and provides evidence of the reversal of maladaptive transcriptional reprogramming in the heart leading to partial restoration of cardiac function.
2022-02-08 | GSE169078 | GEO
Project description:Hypertrophic/dilated cardiomyopathy, often a prequel to heart failure, is accompanied by maladaptive transcriptional changes that contribute to arrythmias and contractile misfunction. Transgenic mice constitutively expressing high levels of calcineurin are known to develop extreme heart hypertrophy, which progresses to dilated cardiomyopathy, and to die several weeks after birth. Here, we characterized aberrant transcriptional and epigenetic pathways in this mouse model and established a pharmacological approach to treat established cardiomyopathy. We found that H3K4me3 (trimethyl histone 3 lysine 4) and H3K9me3 (trimethyl histone 3 lysine 9) Jumonji histone demethylases are markedly increased at the protein level and show enhanced enzymatic activity in diseased hearts. These epigenetic regulators continued to increase with time, further affecting cardiac gene expression. Our findings parallel the lower H3K4me3 and H3K9me3 levels seen in human patients. Inhibition of Jumonji demethylase activities in vivo results in lower histone demethylase enzymatic function in the heart and higher histone methylation levels and leads to partial reduction of heart size, reversal of maladaptive transcriptional programs, improved heart function, and prolonged survival. At the molecular level, target genes of transcription factor myocyte enhancer factor 2 are specifically regulated in response to pharmacological or genetic inhibition of Jumonji demethylases. Similar transcriptional reversal of disease-associated genes is seen in a second disease model based on cardiac mechanical overload. Our findings validate pharmacological inhibitors of Jumonji demethylases as potential therapeutics for the treatment of cardiomyopathies across disease models and provide evidence of the reversal of maladaptive transcriptional reprogramming leading to partial restoration of cardiac function. In addition, this study defines pathways of therapeutic resistance upregulated with disease progression.
| S-EPMC8803621 | biostudies-literature
Project description:Little is known about the role of the three Jumonji C (JmjC) enzymes in Plasmodium falciparum (Pf). Here, we show that JIB-04 and other established inhibitors of mammalian JmjC histone demethylases kill asexual blood stage parasites and are even more potent at blocking gametocyte development and gamete formation. In late stage parasites, JIB-04 increased levels of trimethylated lysine residues on histones, suggesting the inhibition of P. falciparum Jumonji demethylase activity. These epigenetic defects coincide with deregulation of invasion, cell motor, and sexual development gene programs, including gene targets coregulated by the PfAP2-I transcription factor and chromatin-binding factor, PfBDP1. Mechanistically, we demonstrate that PfJmj3 converts 2-oxoglutarate to succinate in an iron-dependent manner consistent with mammalian Jumonji enzymes, and this catalytic activity is inhibited by JIB-04 and other Jumonji inhibitors. Our pharmacological studies of Jumonji activity in the malaria parasite provide evidence that inhibition of these enzymatic activities is detrimental to the parasite.
2020-07-12 | GSE117307 | GEO
Project description:How artificial environmental cues are biologically integrated and transgenerationally inherited is still poorly understood. Here, we investigate the mechanisms of inheritance of reproductive outcomes elicited by the model environmental chemical Bisphenol A (BPA) in C. elegans. We show that BPA exposure causes the derepression of an epigenetically silenced transgene in the germline for 5 generations, regardless of ancestral response. ChIP-seq, histone modifications quantitation, and immunofluorescence assays revealed that this effect is associated with a reduction of the repressive marks H3K9me3 and H3K27me3 in whole worms and in germline nuclei in the F3 as well as with reproductive dysfunctions including germline apoptosis and embryonic lethality. Furthermore, targeting of the Jumonji demethylases JMJD-2 and JMJD-3/UTX-1 restores H3K9me3 and H3K27me3 levels, respectively, and fully alleviates the BPA-induced transgenerational effects. Together, our results demonstrate the central role of repressive histone modifications in the inheritance of reproductive defects elicited by a common environmental chemical exposure.
2018-04-17 | GSE113266 | GEO
Project description:How artificial environmental cues are biologically integrated and transgenerationally inherited is still poorly understood. Here, we investigate the mechanisms of inheritance of reproductive outcomes elicited by the model environmental chemical Bisphenol A (BPA) in C. elegans. We show that BPA exposure causes the derepression of an epigenetically silenced transgene in the germline for 5 generations, regardless of ancestral response. ChIP-seq, histone modifications quantitation, and immunofluorescence assays revealed that this effect is associated with a reduction of the repressive marks H3K9me3 and H3K27me3 in whole worms and in germline nuclei in the F3 as well as with reproductive dysfunctions including germline apoptosis and embryonic lethality. Furthermore, targeting of the Jumonji demethylases JMJD-2 and JMJD-3/UTX-1 restores H3K9me3 and H3K27me3 levels, respectively, and fully alleviates the BPA-induced transgenerational effects. Together, our results demonstrate the central role of repressive histone modifications in the inheritance of reproductive defects elicited by a common environmental chemical exposure.
2018-04-16 | GSE113187 | GEO
Project description:2-Oxoglutarate- and Fe(ii)-dependent oxygenases are a major class of N(epsilon)-methyl lysine demethylases that are involved in epigenetic regulation. Assays suitable for implementation in a high-throughput manner have been lacking for these enzymes. Here, we describe the design and implementation of a robust and miniaturized high-throughput kinetic assay for inhibitors of JMJD2E using a formaldehyde dehydrogenase-coupled reaction with real-time fluorescence detection. Reactant compatibility studies resulted in simplification of the assay scheme to the mixing of two reagent solutions, both of which were stable overnight. The assay was miniaturized to a 4 microL volume in 1536-well format and was used to screen the library of pharmacologically active compounds (LOPAC(1280)). Inhibitors identified by the screen were further characterized in secondary assays including FDH counterscreen and demethylation assays that monitored demethylation by MALDI-TOF MS. The assay developed here will enable the screening of large compound libraries against the Jumonji demethylases in a robust and automated fashion.
| S-EPMC3401096 | biostudies-literature