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Project description:ARRDC4 knock out Mouse Heart Analysis
| PRJNA773414 | ENA
Project description:Spinocerebellar ataxia 3 (SCA3) is a genetic disorder resulting from the expansion of the CAG repeats in the ATXN3 gene. The pathogenesis of SCA3 is based on the toxic function of the mutant ataxin-3 protein, but the exact mechanism of the disease remains elusive. Various types of transgenic mouse models explore different aspects of SCA3 pathogenesis, but a knock-in humanized mouse has not yet been created. The initial aim of this study was to generate an ataxin-3 humanized mouse model using a knock-in strategy. The human cDNA for ataxin-3 containing 69 CAG repeats was cloned from SCA3 patient and introduced into the mouse ataxin-3 locus at exon 2, deleting it along with exon 3 and intron 2. Although the human transgene was inserted correctly, the resulting mice acquired the knock-out properties and did not express ataxin-3 protein in any analyzed tissues, as confirmed by western blot and immunohistochemistry. Analyses of RNA expression revealed that the entire locus consisting of human and mouse exons was expressed and alternatively spliced. We detected mRNA isoforms composed of exon 1 spliced with mouse exon 4 or with human exon 7. After applying 37 PCR cycles, we also detected a very low level of the correct exon 1/exon 2 isoform. Additionally, we confirmed by bioinformatic analysis that the structure and power of the splicing site between mouse intron 1 and human exon 2 (the targeted locus) was not changed compared with the native mouse locus. We hypothesized that these splicing aberrations result from the deletion of further splicing sites and the presence of a strong splicing site in exon 4, which was confirmed by bioinformatic analysis. In summary, we created a functional ataxin-3 knock-out mouse model that is viable and fertile and does not present a reduced life span. Our work provides new insights into the splicing characteristics of the Atxn3 gene and provides useful information for future attempts to create knock-in SCA3 models.
| S-EPMC3044828 | biostudies-literature
Project description:Fibrosis is defined as an abnormal matrix remodeling and loss of tissue homeostasis due to excessive synthesis and accumulation of extracellular matrix proteins in tissues. At present, there is no effective therapy for organ fibrosis. Previous studies demonstrated that aged plasminogen activator inhibitor-1(PAI-1) knockout mice develop spontaneously cardiac-selective fibrosis without affecting any other organs including kidney. Therefore, the PAI-1 knockout model of cardiac fibrosis provides an excellent opportunity to find the igniter(s) of cardiac fibrosis and its status in unaffected organs. We hypothesized that differential expressions of profibrotic and antifibrotic genes in PAI-1 knockout hearts and unaffected organs lead to cardiac selective fibrosis. In order to address this prediction, we have used a genome-wide gene expression profiling of transcripts derived from aged PAI-1 knockout hearts and kidneys. The variations of global gene expression profiling were compared within four groups: wildtype heart vs. knockout heart; wildtype kidney vs. knockout kidney; knockout heart vs. knockout kidney and wildtype heart vs. wildtype kidney. Analysis of illumina-based microarray data revealed that several genes involved in different biological processes such as immune system processing, response to stress, cytokine signaling, cell proliferation, adhesion, migration, matrix organization and transcriptional regulation were affected in hearts and kidneys by the absence of PAI-1, a potent inhibitor of urokinase- and tissue-type plasminogen activator. Importantly, the expressions of a number of genes, involved in profibrotic pathways were upregulated or downregulated in PAI-1 knockout hearts compared to wildtype hearts and PAI-1 knockout kidneys. To our knowledge, this is the first comprehensive report on the influence of PAI-1 on global gene expression profiling in the heart and kidney and its implication in several biological processes including fibrogenesis. Total RNA was extracted from hearts and kidneys derived from three PAI-1 knockout (12- month old) and three wild-type mice (12-month old) using RNeasy Fibrous Tissue Mini Kit (Qiagen, Valencia, CA) following the manufacturer’s instructions. The quality of RNA (RNA Integrity, RIN) in all 12 samples (3 wildtype hearts; 3 PAI-1 KO hearts; 3 wildtype kidneys; and 3 PAI-1 KO kidneys) was checked using the bioanalyzer. We have used a genome-wide gene expression profiling of transcripts derived from aged PAI-1 knockout hearts and kidneys. The variations of global gene expression profiling were compared within four groups: wildtype heart vs. knockout heart; wildtype kidney vs. knockout kidney; knockout heart vs. knockout kidney and wildtype heart vs. wildtype kidney.
2014-04-23 | E-GEOD-46320 | biostudies-arrayexpress
Project description:Deubiquitinases (DUBs) play a role in regulating protein degradation which is critical for maintaining protein homeostasis. The purpose of this study was to verify biological consequence of genetic depletion of USP21 in human cells on proteome changes and cellular function. Comparison of proteomic analysis of HAP-1 USP21 knockout and HAP-1 WT cells revealed that down-regulated proteins in HAP-1 USP21 KO cell are mostly engaged in mitochondrial function and ATP production. Cellular assays confirmed disturbance of mitochondrial metabolism and decrease in ATP production in HAP-1 USP21 knock-out cells.
2024-10-02 | PXD044105 | Pride
Project description:To investigated global changes caused by pressure overload-induced heart failure in ADAM12 knockout mice using a microarray analysis. A disintegrin and metalloproteinase (ADAM) 12 is has long been considered to promote cardiac dysfunction based on according to the finding report that a small molecule ADAM12 inhibitor, KB-R7785 ameliorated cardiac function in a transverse aortic constriction (TAC) model by inhibiting the through inhibition of proteolytic activation of HB-EGF signaling. HoweverOn the other hand, this compound has poor selectivity for ADAM12, and the role of ADAM12 inon cardiac dysfunction has not yet been investigated usingby genetic loss-of-function mice. Anoperation. ADAM12 deficiency resulted in significantly more expanded cardiac fibrosis accompanied byaccompanying with increased collagen-related gene expression in their failing hearts. The results of a genome-wide transcriptional analysis suggested a strongly enhanced highly elevated focal adhesion- and fibrosis-related signaling pathway in ADAM12 knockout hearts. The present results study revealed that the loss of ADAM12 enhanced focal adhesion and canonical TGF-β signaling by regulating the abundance of the integrin β1 and TGF-β receptors.
2019-10-18 | GSE137442 | GEO
Project description:To investigate the role of ketone body in the transcriptome in neonatal mouse heart, we constructed Hmgcs2 knockout mice and performed gene expression profiling analysis using data obtained from RNA-seq of wild-type and Hmgcs2 knockout mouse hearts at postnatal 3rd day.
2022-09-20 | GSE206797 | GEO
Project description:Comparison of the transcriptome of Wildtype versus Murf1/2 double Knock Out (dKO) mouse hearts is analyzed
2008-01-15 | E-MEXP-1321 | biostudies-arrayexpress
Project description:Dilated cardiomyopathy (DCM) is a major risk factor for developing heart failure and is often associated with an increased risk for life-threatening arrhythmia. Although numerous causal genes for DCM have been identified, RNA binding motif 20 (RBM20) remains one of the few splicing factors that, when mutated or genetically ablated, leads to the development of DCM. In this study we sought to identify changes in the cardiac proteome in RBM20 deficient rat hearts using global quantitative proteomics to gain insight into the molecular mechanisms precipitating the development of DCM secondary to RBM20 loss. Our analysis identified changes in titin interacting proteins, as well as mitochondrial enzymes, implicating activation of pathological hypertrophy and mitochondrial dysfunction in DCM development in RBM20 deficient rats. Collectively, our findings provide the first look into changes in the cardiac proteome associated with genetic ablation of RBM20.
2023-05-12 | PXD033429 | Pride
Project description:Inhibitor of growth 4 and 5 (ING4 and ING5) are chromatin-binding proteins in the KAT6A, KAT6B and KAT7 histone acetyltransferase protein complexes. Heterozygous mutations in the KAT6A or KAT6B gene cause human disorders with cardiac defects, but the contribution of their chromatin adaptor proteins to development is unknown. We found that Ing5–/– mice had isolated cardiac ventricular septal defects. ING4 and ING5 are structurally similar proteins, suggesting a degree of redundancy. Combined loss of ING4 and ING5 caused developmental arrest at embryonic day E8.5, loss of histone H3 lysine 14 acetylation (H3K14ac), a reduction in H3K23ac levels and disruption of developmental gene expression in Ing4–/–Ing5–/– compared to control embryos. E12.5 Ing4+/–Ing5–/– hearts showed a paucity of epicardial cells and epicardium-derived cells, failure of myocardium compaction and coronary vasculature defects, accompanied by a reduction in the expression of epicardium genes compared to control hearts. In addition, a reduction in the expression of genes required for cell adhesion, both in whole E8.75 Ing4–/–Ing5–/– embryos and in E10.5 Ing4+/–Ing5–/– hearts compared to controls was observed. In vitro assessment of fibroblast and proepicardium explants revealed cell spreading and outgrowth defects. Our findings suggest that ING4 and ING5 are essential for heart development and promote epicardium and epicardium-derived cell fates and mutation of the human ING5 gene as a possible cause of isolated ventricular septal defects.
2024-02-01 | GSE252338 | GEO
Project description:Genome-wide association identified SLC16A13 as novel type 2 diabetes gene locus. The SLC16A13 gene encodes for SLC16A13/MCT13, member of the solute carrier 16 family of monocarboxylate transporters. This transporter family recently raised interest in metabolic research with the identification of SLC16A11 polymorphisms associated with type 2 diabetes; and human as well as mouse data suggest causal relationship between SLC16A11/MCT11 transporter dysfunction and type 2 diabetes development. In contrast, SLC16A13 biology and physiological function is not characterized at all. Here, we validate SLC16A13 as monocarboxylate transporter expressed at the plasma membrane and report the first Slc16a13 knockout mouse line. Deletion of Slc16a13 ameliorates metabolic disease in the context of diet-induced obesity. The improved metabolic phenotype is characterized by increased mitochondrial respiration in the liver, leading to reduced hepatic lipid accumulation and increased insulin sensitivity of Slc16a13 knockout mice. Mechanistically, we propose reduced intracellular lactate availability in Slc16a13 knockout hepatocytes, affecting hepatic energy metabolism by AMPK activation and increased oxidative phosphorylation, reducing hepatic lipid content and insulin resistance in obese mice. Together, these data suggest SLC16A13/MCT13 as potential novel target to treat fatty liver, insulin resistance and related metabolic disorders.
2021-06-24 | GSE152937 | GEO