USP28-regulated mitochondrial homeostasis mechanism that involves the PPARα-Mfn2 axis in diabetic hearts [ChIP-seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1025893 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26321078_1.fastq.gz | Fastqsanger.gz | |||
| SRR26321078_2.fastq.gz | Fastqsanger.gz | |||
| SRR26321079_1.fastq.gz | Fastqsanger.gz | |||
| SRR26321079_2.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 4 of 4 |
Similar Datasets
Project description:The majority of diabetics are susceptible to cardiac dysfunction and heart failure, while conventional drug therapy cannot correct diabetic cardiomyopathy (DCM) progression. Herein, we assessed the potential role and therapeutic value of ubiquitin-specific protease 28 (USP28) on the metabolic vulnerability of DCM. PPARα-/- in the db/db background mice were constructed to check the mechanism of USP28 in vivo. Inducible cardiac-specific deletion of Mfn2 in the db/db background mice was utilized to evaluate USP28-mediated cardioprotection. chromatin immunoprecipitation (ChIP) assays revealed that PPARα promote mitofusin 2 (Mfn2) transcription, thereby impeding mitochondrial morphofunctional defects.
2023-10-15 | GSE244905 | GEO
Project description:The majority of diabetics are susceptible to cardiac dysfunction and heart failure, while conventional drug therapy cannot correct diabetic cardiomyopathy (DCM) progression. Herein, we assessed the potential role and therapeutic value of ubiquitin-specific protease 28 (USP28) on the metabolic vulnerability of DCM. cardiac USP28 deficient diabetic mice showed cardiac dysfunction, lipid accumulation, and mitochondrial disarrangement, compared to their controls. Conversely, USP28 overexpression improved systolic and diastolic dysfunction and ameliorated cardiac hypertrophy and fibrosis in the diabetic heart. Mechanistically, USP28 directly interacted with peroxisome proliferator-activated receptor α (PPARα), deubiquitinating and stabilizing PPARα (Lys152) to promote mitofusin 2 (Mfn2) transcription, thereby impeding mitochondrial morphofunctional defects.
2023-10-15 | GSE244904 | GEO
Project description:Usp28-KO HLF cell lines were generated by CRISPR-Cas9. Usp28-KO cells expressing Usp28-WT, Usp28-Mono or a control vector were established by lentiviral transduction.
2023-09-30 | GSE213892 | GEO
Project description:Fbw7, the substrate recognition subunit of SCF(Fbw7) ubiquitin ligase, mediates turnover of multiple proto-oncoproteins and promotes its own degradation. Fbw7-mediated substrate degradation is antagonized by the Usp28 deubiquitinase. We now show, using knockout mice, that Usp28 preferentially deubiquitinates and stabilizes Fbw7. Monoallelic deletion of Usp28 maintains stable Fbw7 but destabilizes Fbw7 substrates. In contrast, complete knockout of Usp28 promotes Pin1-dependent autocatalytic turnover of Fbw7, accumulation of Fbw7 substrates and oncogenic transformation. Overexpression of Usp28 stabilizes both Fbw7 and its substrates and similarly enhances transformation. We propose that dual regulation of Fbw7 activity by Usp28 maintains physiological levels of Fbw7 substrates, and that both loss and overexpression of Usp28 in human cancer promote Fbw7 substrate accumulation. RNAseq experiments of E13.5 murine embryonic fibroblasts (MEFs) derived from animals in which Usp28 was either deleted (-/-), wildtype (+/+) or heterozygous (+/-). In a first set of experiments immortalized MEFs of all three genotypes were analysed in biological triplicates. In a second set of experiments immortalized and Ras transformed MEFs of all three genotypes and MEFs which overexpress USP28 (+/+/+) where sequenced in duplicates.
2015-05-01 | E-GEOD-59354 | biostudies-arrayexpress
Project description:Inter-organelle contact and communication between mitochondria (Mito) and endoplasmic reticulum (ER), also known as sarcoplasmic reticulum (SR) in cardiomyocytes (CM), play vital roles in the maintenance of Mito and SR properties and cellular homeostasis. Here, we tested the hypothesis that the formin, Diaphanous-1 (DIAPH1), which regulates actin dynamics and signal transduction, contributes to these processes. Mice bearing CM-specific deletion of Diaph1 displayed reduced injury and superior functional recovery after the induction of cardiac ischemia and reperfusion (I/R). Studies in DIAPH1-silenced human induced pluripotent stem cell-derived CMs (HiPSC-CMs) and murine hearts devoid of CM-Diaph1 revealed that DIAPH1 interacts directly with Mitofusin-2 (MFN2) to regulate Mito-SR contact, Mito turnover, mitophagy, and oxidative stress. Ischemic murine hearts and human heart biopsies revealed more robust DIAPH1-MFN2 interaction vs. that observed in non-ischemic hearts. Solution structure studies affirm this interaction and reveal strong pH-dependent interaction between the Diaphanous Inhibitory Domain (DID) and the cytosolic GTPase domain of MFN2. In HiPSC-CMs, introduction of synthetic linkers, which reduce the Mito-SR distance, mitigated the cardioprotective benefits of Diaph1 deletion. Finally, DIAPH1 binding to the cytoplasmic domain of receptor for advanced glycation endproduct (RAGE) supports signal transduction and contributes to I/R injury in the heart; in HiPSC-CMs, small molecule antagonism of RAGE-DIAPH1 reduced DIAPH1-MFN2 interaction and increased Mito-SR distance. This work establishes fundamental roles for DIAPH1-MFN2 interaction in the regulation of Mito-SR contact networks that control responses to ischemic stress. Targeting pathways that regulate DIAPH1-MFN2 may facilitate recovery from cardiac ischemic injury.
2022-09-28 | GSE214149 | GEO
Project description:Fbw7, the substrate recognition subunit of SCF(Fbw7) ubiquitin ligase, mediates turnover of multiple proto-oncoproteins and promotes its own degradation. Fbw7-mediated substrate degradation is antagonized by the Usp28 deubiquitinase. We now show, using knockout mice, that Usp28 preferentially deubiquitinates and stabilizes Fbw7. Monoallelic deletion of Usp28 maintains stable Fbw7 but destabilizes Fbw7 substrates. In contrast, complete knockout of Usp28 promotes Pin1-dependent autocatalytic turnover of Fbw7, accumulation of Fbw7 substrates and oncogenic transformation. Overexpression of Usp28 stabilizes both Fbw7 and its substrates and similarly enhances transformation. We propose that dual regulation of Fbw7 activity by Usp28 maintains physiological levels of Fbw7 substrates, and that both loss and overexpression of Usp28 in human cancer promote Fbw7 substrate accumulation.
2015-05-01 | GSE59354 | GEO
Project description:To investigate the role of USP28 expression in chronic lymphocytic leukemia, we used the CRISPR/Cas9 system to engineer isogenic HG3 cell lines harboring a monoallelic USP28 loss. We then analyzed the transcriptomic profile of these CRISPR/Cas9-generated cell lines by RNA-seq
2025-05-31 | GSE229756 | GEO
Project description:Autophagy is an evolutionally conserved catabolic process that recycles nutrients upon starvation and maintains cellular energy homeostasis1-3. Its acute regulation by nutrient sensing signaling pathways is well described, but its longer-term transcriptional regulation is not. The nuclear receptors PPARα and FXR are activated in the fasted or fed liver, respectively4,5. Here we show that both regulate hepatic autophagy. Pharmacologic activation of PPARα reverses the normal suppression of autophagy in the fed state, inducing autophagic lipid degradation, or lipophagy. This response is lost in PPARα knockout (PPARα-/-) mice, which are partially defective in the induction of autophagy by fasting. Pharmacologic activation of the bile acid receptor FXR strongly suppresses the induction of autophagy in the fasting state, and this response is absent in FXR knockout (FXR-/-) mice, which show a partial defect in suppression of hepatic autophagy in the fed state. PPARα and FXR compete for binding to shared sites in autophagic gene promoters, with opposite transcriptional outputs. These results reveal complementary, interlocking mechanisms for regulation of autophagy by nutrient status. Mouse liver PPARα cistromes in fed 8-week-old male WT or PPARα KO mice treated with or without its synthetic agonist ligand GW7647twice a day were generated by deep sequencing in quadruplicate using illumina
2014-09-27 | E-GEOD-61817 | biostudies-arrayexpress
Project description:PARP inhibitor (PARPi) resistance presents a significant challenge in ovarian cancer treatment, necessitating the development of effective therapeutic strategies to overcome this resistance and improve patient outcomes. Our study demonstrated that elevated expression of SRY-box 9 (SOX9) contributes to olaparib resistance in ovarian cancer. Mechanistically, the deubiquitinating enzyme USP28 was identified as a novel interacting partner of SOX9. USP28 inhibited the ubiquitination and subsequent lysosomal degradation of SOX9, which is mediated by the E3 ubiquitin ligase FBXW7 during olaparib treatment. ChIP-Seq analysis revealed that SOX9 binds to the promoters of key DNA damage response (DDR) genes (SMARCA4, UIMC1, and SLX4), thereby regulating DDR processes in ovarian cancer. Additionally, USP28 promoted olaparib resistance by stabilizing SOX9 protein and enhancing DNA damage repair. Furthermore, the USP28 specific inhibitor AZ1 reduced SOX9 protein stability and increased the sensitivity of ovarian cancer cells to olaparib. In conclusion, targeted inhibition of USP28 promoted ubiquitination-mediated degradation of SOX9, thereby impairing DNA damage repair capabilities and sensitizing ovarian cancer cells to PARPi. These findings elucidate the underlying mechanisms of PARPi resistance in ovarian cancer and suggest the potential efficacy of combining USP28 inhibitors with PARPi to overcome this resistance.
2025-04-23 | GSE271296 | GEO
Project description:For validating the role Usp28 in regulating mouse ESC self-renewal, sgRNAs were designed to generate Usp28 KO cell lines. We then performed gene expression profiling analysis using data obtained from RNA-seq control (CTL) and Usp28 KO ESCs.
2023-05-01 | GSE229112 | GEO