Downregulation of SENP1 impairs nuclear condensation of MEF2C and deteriorates ischemic cardiomyopathy
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1200582 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31775992_1.fastq.gz | Fastqsanger.gz | |||
| SRR31775992_2.fastq.gz | Fastqsanger.gz | |||
| SRR31775993_1.fastq.gz | Fastqsanger.gz | |||
| SRR31775993_2.fastq.gz | Fastqsanger.gz | |||
| SRR31775994_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 12 |
Similar Datasets
Project description:Ischemic cardiomyopathy (ICM) is characterized by the insufficient capacity of the heart to effectively pump blood, which ultimately contributes to heart failure (HF). In this study, the down regulation of SNEP1 is identified in the cardiomyocyte of ICM mouse models and in patients. The depletion of SENP1 exacerbates hypoxia-induced apoptosis of cardiomyocytes in vitro and deteriorated cardiomyocyte injury of ICM mice in vivo. Mechanistically, SENP1 directly interacted and deSUMOylates the SUMO2-mediated modification of MEF2C at lysine 407, consequently promoting the protein stability and phase separation of MEF2C. When rescuing SENP1 expression using adeno-associated virus serotype 9, the attenuation of cardiomyocyte injury is discerned in the mouse model of ICM. Therefore, these finding elicits a previously unrecognized role and mechanism of SENP1 in safeguarding cardiomyocyte in ICM progression while establishing a basis for the development of SENP1 as a potential marker for ICM diagnosis and treatment.
2025-05-14 | GSE284743 | GEO
Project description:The mechanism underlying RIPK1-driven cell death and inflammation, a key process in the progression of nonalcoholic steatohepatitis, remains unclear. Here we identified SENP1, a SUMO-specific protease, as a key endogenous inhibitor of RIPK1. SENP1 is progressively reduced in proportion to NASH severity in patients. Hepatocyte-specific SENP1-knockout mice develop spontaneous NASH-related phenotypes in a RIPK1 kinase-dependent manner. We demonstrate that SENP1 deficiency sensitizes cells to RIPK1 kinase-dependent apoptosis by promoting RIPK1 activation following TNFα stimulation. Mechanistically, SENP1 deSUMOylates RIPK1 in TNF-R1 signaling complex (TNF-RSC), keeping RIPK1 in check. Loss of SENP1 leads to SUMOylation of RIPK1, which re-orchestrates TNF-RSC and modulates the ubiquitination patterns and activity of RIPK1. Notably, genetic inhibition of RIPK1 effectively reverses disease progression in hepatocyte-specific SENP1-knockout male mice with high-fat-diet-induced nonalcoholic fatty liver. We propose that deSUMOylation of RIPK1 by SENP1 provides a pathophysiologically relevant cell death-restricting checkpoint that modulates RIPK1 activation in the pathogenesis of nonalcoholic steatohepatitis.
2022-10-20 | GSE193509 | GEO
Project description:Carfilzomib has a good effect in treating multiple myeloma, but more and more clinical studies have shown that the drug can cause cardiac toxicity during use, but the mechanism of action is unclear. This study aimed to comprehensively elucidate the mechanism of CFZ-induced cardiomyopathy by constructing a C57BL/6 mouse model and combining cell experiments. The research results showed that the hearts of mice treated with CFZ appeared significantly enlarged, and the cardiac function indicators decreased. The serum enzyme LDH, AST, and CK-MB levels significantly increased, suggesting severe myocardial injury. RNA extraction and QPCR detection of the heart showed that the expression of heart hypertrophy and fibrosis markers increased. Meanwhile, histological staining found that there were fewer cardiomyocytes, damaged myofibrils, and cardiac fibrosis. In the cell experiments, CFZ treatment caused the release of more LDH from rat cardiomyocytes and H9C2 cells, increased CASPASE 3/7 activity, abnormal cell morphology, enlarged cell size, myocardial hypertrophy and fibrosis marker gene expression in cardiomyocytes. Through the study of the SUMOYLATION pathway, it was found that CFZ's effects on cardiomyocyte structure and function were related to the expression of SENP genes, especially SENP1, which showed a significant downregulation in cardiomyocytes and mouse heart tissue, and was positively correlated with the levels of cardiac injury marker genes. This study further explored the mechanism of action by specifically altering the expression of SENP1 in cardiomyocytes. The results show that the knockdown of SENP1 in cardiomyocytes leads to more severe myocardial damage after CFZ treatment, suggesting that the expression of SENP1 can potentially affect the cardiotoxicity caused by CFZ. Further, by using silver staining and mass spectrometry to identify the interacting proteins with SENP1 after CFZ treatment, we found that the knockdown of DDX17 had a similar myocardial injury effect as SENP1. Subsequently, through Co-IP, protein stability experiments, and ubiquitination analysis experiments, we determined that SENP1 can maintain the protein stability of DDX17 by inhibiting its SUMO modification, thereby preventing cardiomyocyte injury and apoptosis. We hope to provide a new perspective and potential cardioprotective strategy for clinical use.
2024-08-10 | GSE273971 | GEO
Project description:Humoral immunity depends on germinal center reaction where B cells are tightly controlled for class switch recombination (CSR) and somatic hypermutation, and finally generated into plasma and memory B cells. However, how protein SUMOylation control the key events of GC B cells remains to be understood. Here, we show that SUMO-specific protease 1 (SENP1) is upregulated in GC B cells. Selective ablation of Senp1 within GC B cells led to defective dark zone versus light zone GC B organization, impaired IgG1-switched GC B cells, and compromised antibody response. In addition, the formation of antigen-specific plasma and memory B cells were also diminished when SENP1 was deleted in GC B cells. Mechanistically, SENP1 was indispensable for expression of activation-induced cytidine deaminase (AID). SENP1-mediated Paired box protein 5 deSUMOylation suppressed the transcription to AID, which might be responsible for defective CSR in vivo. Our study not only established the importance of protein SUMOylation for the maintenance of GC B cell function but also clarified a novel mechanism to the modulation of AID expression.
2024-06-12 | GSE227067 | GEO
Project description:Pancreatic β-cells respond to metabolic stress by upregulating insulin secretion, however the underlying mechanisms remain unclear. In β-cells from overweight humans without diabetes, and mice fed a high-fat diet for 2 days, insulin exocytosis and secretion are enhanced without increased Ca2+ influx. β-cell RNA-seq suggests altered metabolic pathways early following HFD, where we find increased basal oxygen consumption, proton leak, but a more reduced cytosolic redox state. Increased β-cell exocytosis after 2-day HFD is dependent on this reduced intracellular redox, and requires the sentrin-specific SUMO-protease-1 (SENP1). Mice with either pancreas- or β-cell-specific SENP1 deletion fail to up-regulate exocytosis and become rapidly glucose intolerant after 2-day HFD. Mechanistically, redox-sensing by SENP1 requires a thiol group at C535 which together with Zn+-binding suppresses basal protease activity and unrestrained β-cell exocytosis, and increases SENP1 sensitivity to regulation by redox signals.
2023-12-15 | GSE249790 | GEO
Project description:Identification of peptides matching to LCK in SENP1 immunoprecipitates from Jurkat E6.1 T cells by mass spectrometry
2022-01-13 | PXD029720 | Pride
Project description:Microdeletions of the MEF2C gene are linked to a syndromic form of autism termed MEF2C haploinsufficiency syndrome (MCHS). Here, we show that MCHS-associated missense mutations cluster in the conserved DNA binding domain and disrupt MEF2C DNA binding. DNA binding-deficient global Mef2c heterozygous mice (Mef2c-Het) display numerous MCHS-like behaviors, including autism-related behaviors, as well as deficits in cortical excitatory synaptic transmission. We find that hundreds of genes are dysregulated in Mef2c-Het cortex, including significant enrichments of autism risk and excitatory neuron genes. In addition, we observe an enrichment of upregulated microglial genes, but not due to neuroinflammation in the Mef2c-Het cortex. Importantly, conditional Mef2c heterozygosity in forebrain excitatory neurons reproduces a subset of the Mef2c-Het phenotypes, while conditional Mef2c heterozygosity in microglia reproduces social deficits and repetitive behavior. Together our findings suggest that MEF2C regulates typical brain development and function through multiple cell types, including excitatory neuronal and neuroimmune populations.
2020-10-24 | GSE139419 | GEO
Project description:In acute myeloid leukemia, chemotherapy resistance remains prevalent and poorly understood. Using functional proteomics of patient AML specimens, we identified MEF2C S222 phosphorylation as a specific marker of primary chemoresistance. We found that transgenic Mef2cS222A/S222A mice engineered to block MEF2C phosphorylation exhibited normal hematopoiesis, but were resistant to leukemogenesis induced by MLL-AF9. MEF2C phosphorylation was required for leukemia stem cell maintenance, induced by MARK kinases in cells, and blocked by selective MARK inhibitor MRT199665, which caused apoptosis of MEF2C-activated human AML cell lines and primary patient specimens, but not those lacking MEF2C. These findings identify signaling-dependent dysregulation of transcription factor control as a determinant of therapy response in AML, with immediate potential for improved diagnosis and therapy for this disease.
2018-07-23 | GSE94453 | GEO
Project description:The transcription factor MEF2C is specifically induced by VEGF in endothelial cells. To delineate target genes of MEF2C in endothelial cells, which might be important during angiogenesis also, MEF2C was overexpressed adenovirally in human umbilical vein endothelial cells (HUVECs) over a period of 8 to 32 hours. Expression data should be compared to control infected cells, to discriminate against virally induced genes, and should be further compared to HUVECs infected with an adenovirus encoding for a dominant-negative form of MEF2. HUVECs of the same batch, passage 3 were infected with Ad.con, Ad.MEF2C or Ad.DNMEF2 for 8, 16 or 32 hours for RNA extraction and hybridization on Affymetrix microarrays.
2013-06-01 | E-GEOD-46279 | biostudies-arrayexpress
Project description:MEF2C is one of the substantially expressed transcriptional factors in endothelial cells, but its genomic localization is unknown. This time, we established a new antibody for MEF2C, and performed ChIP-seq to identify MEF2C binding site in whole genome manner. H3K27Ac binding sites were also detected in the same way. We used chromatin immunoprecipitation with deep sequencing (ChIP-seq) of HUVECs treated with or without pitavastatin for 4hours, we identified MEF2C and H3K27Ac binding regions.HUVECs were used within the first 6 passages. For MEF2C studies, HUVECs were cultivated in medium EGM2MV containing pitavastatin at a concentration of 1 ?M, and same concentration of DMSO was used as a control sample. For H3K27ac, HUVECs were starved for 16 hours and harvested without statin treatment.
2013-01-01 | E-GEOD-32644 | biostudies-arrayexpress