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Oridonin as a Novel KDM5C Inhibitor Alleviates Clonal Hematopoiesis Induced Cardiac Aging via H3K4me3 Dependent SASP Suppression [RNA-seq]

ABSTRACT: We applied Tet2⁺/⁻ bone marrow transplantation (BMT) mouse model to investigate the contribution of clonal hematopoiesis to cardiac aging. A transcriptome-guided small-molecule screening strategy was employed to identify potential therapeutic compounds. Target validation involved molecular docking, enzymatic inhibition, and surface plasmon resonance assays. Genetic and pharmacological perturbation experiments were conducted to examine pathway involvement. Tet2⁺/⁻-BMT mice exhibited age-progressive myocardial fibrosis, inflammation, senescence, and functional decline. Oridonin reversed CHIP- and aging-associated transcriptional signatures and attenuated cardiac remodeling. Mechanistically, oridonin inhibited KDM5C histone demethylase. Downregulation of the pro-senescent factor S100A8 and suppression of SASP-associated inflammation were observed.

ORGANISM(S): Mus musculus

PROVIDER: GSE299167 | GEO | 2025/06/08

REPOSITORIES: GEO

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Oridonin as a Novel KDM5C Inhibitor Alleviates Clonal Hematopoiesis Induced Cardiac Aging via H3K4me3 Dependent SASP Suppression [ChIP-seq]

Project description:We applied Tet2⁺/⁻ bone marrow transplantation (BMT) mouse model to investigate the contribution of clonal hematopoiesis to cardiac aging. A transcriptome-guided small-molecule screening strategy was employed to identify potential therapeutic compounds. Target validation involved molecular docking, enzymatic inhibition, and surface plasmon resonance assays. Epigenetic regulation was assessed using chromatin immunoprecipitation sequencing (ChIP-seq) and transcriptomic profiling. Genetic and pharmacological perturbation experiments were conducted to examine pathway involvement.Genetic manipulation confirmed the KDM5C–SIRT2–SASP regulatory axis mediates oridonin’s effects.TET2-driven clonal hematopoiesis promotes cardiac aging via inflammatory and epigenetic pathways. These finding point that oridonin, as a novel epigenetic modulator, attenuates myocardial dysfunction by inhibiting the KDM5C–SIRT2–SASP axis, supporting its potential as a targeted therapeutic candidate for CHIP-associated cardiac aging.

2025-06-08 | GSE299168 | GEO

Oridonin as a Novel KDM5C Inhibitor Alleviates Clonal Hematopoiesis Induced Cardiac Aging via H3K4me3 Dependent SASP Suppression [RNA-seq]

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Oridonin delays aging through AKT signaling pathway

Project description:Oridonin delays aging through AKT signaling pathway

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NO001: Kdm5c controls promoter and enhancer activities

Project description:The functional organization of eukaryotic genomes correlates with specific patterns of histone methylations. Regulatory regions in genomes like enhancers and promoters differ in their extent of methylation of histone H3 at lysine-4 (H3K4), but it is largely unknown how the different methylation states are specified and controlled. Here, we show that the Kdm5c/Jarid1c/SMCX member of the Kdm5 family of H3K4 demethylases can be recruited to both enhancer and promoter elements in embryonic stem cells and neuronal progenitor cells via gene-specific transcription factors. Knockdown of Kdm5c deregulates transcription via local increases in H3K4me3. Our data show that restricting H3K4me3 modification at core promoters dampens transcription, but Kdm5c is required at enhancers for their full activity. Remarkably, an impaired enhancer function activates the intrinsic promoter activity of Kdm5c-bound distal elements. Our results demonstrate that the Kdm5c demethylase plays a crucial and dynamic role in the functional discrimination between enhancers and core promoters. RNA from four independent cultures from each sh Kdm5c #1, sh Kdm5c #2 and non-targeting shRNA polyclonal cell lines were hybridized in dye-swap against a common reference of RNA from IB10 ES cells.

2013-04-05 | E-GEOD-38862 | biostudies-arrayexpress

The Kdm5c histone demethylase controls enhancer and promoter function.

Project description:Here, we show that the Kdm5c/Smcx member of the Jarid1 family of H3K4 demethylases is recruited to both enhancer and core promoter elements in ES and neuronal progenitor cells (NPC). Knockdown of Kdm5c deregulates transcription via a local increase in H3K4me3. While at core promoters the function of Kdm5c is to restrict transcription, loss of Kdm5c impairs enhancer function. Remarkably, an impaired enhancer function activates promoter activity from Kdm5c-bound intergenic regions. Our results demonstrate that the Kdm5c demethylase plays a crucial role in the functional identity and discrimination of enhancers and core promoters. We speculate that this is related to recruitment of H3K4me3 binders like the TFIID and NURF complexes6-8. Providing functional identity to genomic regions through balancing enzymes that deposit and remove histone modifications may prove to be a general epigenetic mechanism for the functional indexing of eukaryotic genomes. Examination of the KDM5C binding sites in mouse embryonic stem cells and in neuronal progenitor cells. Effect of KDM5C knock down on H3K4me3 and H3K4me1 levels and gene expression.

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