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Inhibition of Jumonji demethylases transcriptionally reprograms severe cardiac hypertrophy and prolongs survival

ABSTRACT: Inhibition of Jumonji demethylases transcriptionally reprograms severe cardiac hypertrophy and prolongs survival

PROVIDER: PRJNA714236 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	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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Inhibition of Jumonji demethylases transcriptionally reprograms severe cardiac hypertrophy and prolongs survival.

Project description:Inhibition of Jumonji demethylases transcriptionally reprograms severe cardiac hypertrophy and prolongs survival.

| PRJNA733239 | ENA

Inhibition of Jumonji demethylases transcriptionally reprograms severe cardiac hypertrophy and prolongs survival

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

Inhibition of Jumonji demethylases transcriptionally reprograms severe cardiac hypertrophy and prolongs survival.

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Inhibition of Jumonji demethylases transcriptionally reprograms severe cardiac hypertrophy and prolongs survival: part 2.

Project description:Inhibition of Jumonji demethylases transcriptionally reprograms severe cardiac hypertrophy and prolongs survival: part 2.

| PRJNA715174 | ENA

Inhibition of Jumonji demethylases transcriptionally reprograms severe cardiac hypertrophy and prolongs survival: part 2.

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Histone succinylation directly inhibits Jumonji domain demethylases and stabilizes repressive chromatin states [CUT&Tag]

Project description:We investigate the relationship between histone succinylation and Jumonji C (JmjC) domain-containing histone demethylases, a class of enzymes that catalyzes the removal of histone methylation. By using quantitative proteomics and peptide pull-down assays, we identified Jumonji demethylases as candidate interactors of succinylated histone peptides. Biochemical assays demonstrate that succinylated histone peptides bind and inhibit the demethylase activity of KDM4D and KDM6B in a dose-dependent manner. Notably, these two demethylases are responsible for the removal of the silencing marks H3K9me2/3 and H3K27me2/3. We increased histone succinylation in a HepG2/C3A cell model by providing supraphysiological sodium succinate and demonstrated that H3K9me2/3 and H3K27me2/3 increased in relative abundance as well. CUT&Tag and ChIP–mass spectrometry revealed co-occurrence of succinylation with repressive methylation marks, together with reduced levels of transcribed RNA. Altogether, these findings support a model in which histone succinylation contributes to maintaining the silencing marks H3K9me2/3 and H3K27me2/3 on chromatin by locally inhibiting Jumonji domain demethylases. This work establishes a mechanistic link between metabolic state and chromatin regulation and suggests a role for histone succinylation in the maintenance of heterochromatin.

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Histone succinylation directly inhibits Jumonji domain demethylases and stabilizes repressive chromatin states [RNA-Seq]

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