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

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

PROVIDER: PRJNA1273017 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR33855589_1.fastq.gz	Fastqsanger.gz
	SRR33855589_2.fastq.gz	Fastqsanger.gz
	SRR33855590_1.fastq.gz	Fastqsanger.gz
	SRR33855590_2.fastq.gz	Fastqsanger.gz
	SRR33855591_1.fastq.gz	Fastqsanger.gz

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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]

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. 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.

2025-06-08 | GSE299167 | GEO

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

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

| PRJNA1273018 | ENA

Oridonin delays aging through AKT signaling pathway

Project description:Aging is the major risk factor for chronic diseases and disability in human. There is no effective anti-aging clinical treatment. In this study, oridonin was selected based on the drug screening strategy of Connectivity MAP (CMAP) upon transcriptomes of 102 traditional Chinese medicines (TCM) treated cell lines. Oridonin is an anti-inflammatory drug and diterpenoid isolated from Rabdosia rubescens. Oridonin exhibited a variety of pharmacological activities, including anti-tumor, antibacteria and anti-inflammation. Here, we found that oridonin inhibited cellular senescence in human diploid fibroblasts (2BS and WI-38), indicated by decreased senescence-associated β-galactosidase (SA-β-gal) staining. Compared with the elderly control group, the positive cell rate in the oridonin intervention group was 48.5%, and the cell shape was similar to young cells. Oridonin prolonged the lifespan of yeast by 14.6%~48.9%, and prolonged the average life span of naturally aged mice by 21.6%. It also increased the healthspan of aged mice. In addition, oridonin also improved doxorubicin-induced cellular senescence and mouse senescence. Compared with the model group, the percentage of SA-β-gal positive cells in the oridonin treatment group was reduced to 59.8%. It prolonged the average life span of mice by 53.8% as well as the healthspan. Mechanistically, we show that oridonin delayed aging through the AKT signaling pathways and reverses the genetic changes caused by doxorubicin-induced cell senescence. Therefore, oridonin may be an ideal candidate for the development of anti-aging drugs, and it also provides therapeutic potential in other diseases.

2022-03-18 | GSE189789 | GEO

Transcriptome sequencing (RNA-Seq) of HepG2 cells upon treatment of the 10μM Oridonin or DMSO(0.1%)for exploring the metabolic mechanism of Oridonin

Project description:Oridonin is a nature diterpenoid mainly isolated from Chinese herb Rabdosia rubescens and other Isodon species. Nowadays, most of studies focused on the pharmacological effects of oridonin, the metabolism of which remains unclear. In order to investigate the effect of oridonin on metabolism-related genes, we used the second-generation transcriptome sequencing(RNA-seq) to determine the expression changes of each gene in HepG2 cells treated with oridonin.

2021-04-09 | GSE112908 | GEO

The combination of SLC7A11 inhibitor and oridonin synergistically inhibits cervical cancer cell growth by decreasing the NADPH/NADP+ ratio

Project description:Oridonin, as a natural terpenoids isolated from traditional Chinese medicinal herb Rabdosia rubescens, exhibits anticancer activity against multiple cancers with the IC50 ranging from 10 ¦ÌM to 100 ¦ÌM. We observed that SLC7A11 inhibitor Imidazole ketone erastin (1 ¦ÌM) potently increase the anti-proliferative activity of oridonin at low concentrations. Preliminary investigation demonstrated that combination of Imidazole ketone erastin (1 ¦ÌM) and oridonin induced apoptosis and ferroptosis only in a fraction of cells. To explore the synergistic anti-tumor mechanism of combination of oridonin and Imidazole ketone erastin, second-generation transcriptome sequencing(RNA-seq) was utilized to determine the transcriptome change in Hela cells affected by oridonin and Imidazole ketone erastin. PCA analysis showed that the group of oridonin or Imidazole ketone erastin alone located near the control group, while the group of combination gathered far away from the control group, indirectly indicating that combination of oridonin and Imidazole ketone erastin had synergistic biology function.

2023-12-31 | GSE193751 | GEO

Gene expression signatures in oridonin-treated WT and R878H hematopoietic stem cells

Project description:Analysis of WT-Ctl v.s. WT-Ori and R878H-Ctl v.s. R878H-Ori hematopoietic stem cell (lineage-, c-kit+ Sca-1+ CD150+, CD34-). The four population of hematopoietic stem cell (HSC) were purified from the bone marrow of WT and R878H recipent mice treated with vehicle or oridonin. Results provide insight into the role of oridonin in R878H HSC.

2021-05-13 | GSE174362 | GEO

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.

2013-04-01 | E-GEOD-34975 | biostudies-arrayexpress

NO001: Kdm5c controls promoter and enhancer activities

Project description: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-MTAB-1177 | biostudies-arrayexpress

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