Project description:We performed chromatin immunoprecipitation (ChIP) against the core subunit INO80 to determine its direct regulation on downstream targets.
Project description:In order to detect the effect of INO80 on chromatin accessibility, we will utilize the Assay for Transposase Accessible Chromatin with highthroughput sequencing (ATAC-Seq).
Project description:Actr5 is one of the subunits of the ATPase-dependent chromatin remodeling complex INO80. In muscle tissues such as skeletal muscle, heart, and aorta, the expression of Actr5 is much lower than that in non-muscle tissues. During skeletal and smooth muscle development, it interacts with transcription factors such as MyoD, MyoG, SRF, and myocardin to play a repressive role in muscle differentiation, but its physiological role in cardiac development is not entirely clear. To investigate the role of Actr5 in the heart, AAV6 expression vectors containing Actr5 gene were infected into mice, and total RNA were extracted from the heart, followed by DNA microarray analysis.
Project description:Atherosclerosis and pressure overload are major risk factors for the development of heart failure in patients. Cardiac hypertrophy often precedes the development of heart failure. However, underlying mechanisms are incompletely understood. To investigate pathomechanisms underlying the transition from cardiac hypertrophy to heart failure we used experimental models of atherosclerosis- and pressure overload-induced cardiac hypertrophy and failure, i.e. apolipoprotein E (apoE)-deficient mice, which develop heart failure at an age of 18 months, and non-transgenic C57BL/6J (B6) mice with heart failure triggered by 6 months of pressure overload induced by abdominal aortic constriction (AAC). The development of heart failure was monitored by echocardiography, invasive hemodynamics and histology. The microarray gene expression study of cardiac genes was performed with heart tissue from failing hearts relative to hypertrophic and healthy heart tissue, respectively. The microarray study revealed that the onset of heart failure was accompanied by a strong up-regulation of cardiac lipid metabolism genes involved in fat synthesis, storage and oxidation. Microarray gene expression profiling was performed with heart tissue isolated from (i) 18 month-old apoE-deficient mice relative to age-matched non-transgenic C57BL/6J (B6) mice, (ii) 6 month-old apoE-deficient mice with 2 months of chronic pressure overload induced by abdominal aortic constriction (AAC) relative to sham-operated apoE-deficient mice and nontransgenic B6 mice, (iii) 10 month-old B6 mice with 6 months of AAC relative to sham-operated B6 mice, and (iv) 5 month-old B6 mice with 1 month of AAC relative to age-matched B6 mice.
Project description:Depletion of cardiac ATP content is a characteristic feature of heart failure in patients and experimental animal models. To analyze the impact of insufficient ATP supply on heart function we inhibited cellular respiration by disulfide poisoning with the mild thiol-blocking agent, cystamine. We chose 4 month-old apolipoprotein E (apoE)-deficient mice, which are highly vulnerable to increased oxygen and ATP demands. After 4 weeks of cystamine treatment (300 mg/kg in drinking water), echocardiography and histology analyses demonstrated that apoE-deficient mice had developed heart failure with cardiac dilation. The microarray gene expression study of heart tissue from cystamine-treated apoE-deficient mice relative to untreated mice confirmed the development of heart failure showing up-regulation heart failure-specific genes by mild thiol-blocking with cystamine. Microarray gene expression profiling was performed with heart tissue isolated from three study groups: (i) cystamine-treated 5 month-old apolipoprotein- (apoE)- deficient mice with symptoms of heart failure, (ii) untreated 5 month-old apoE- deficient mice, and (iii) age-matched, untreated, non-transgenic B6 control mice.
Project description:Heart failure remains a major unmet clinical need and current therapies targeting neurohomonal and hemodynamic regulation have limited efficacy. We report that pharmacological activation of the transcriptional repressor REV-ERBa prevents expression of a pathological gene program and cardiomyocyte hypertrophy. In vivo, REV-ERBa agonism prevents development and halts progression of heart failure in mouse models. Thus, modulation of gene networks by targeting REV-ERBa represents a novel approach to heart failure therapy.
Project description:Atherosclerosis and pressure overload are major risk factors for the development of heart failure in patients. Cardiac hypertrophy often precedes the development of heart failure. However, underlying mechanisms are incompletely understood. To investigate pathomechanisms underlying the transition from cardiac hypertrophy to heart failure we used experimental models of atherosclerosis- and pressure overload-induced cardiac hypertrophy and failure, i.e. apolipoprotein E (apoE)-deficient mice, which develop heart failure at an age of 18 months, and non-transgenic C57BL/6J (B6) mice with heart failure triggered by 6 months of pressure overload induced by abdominal aortic constriction (AAC). The development of heart failure was monitored by echocardiography, invasive hemodynamics and histology. The microarray gene expression study of cardiac genes was performed with heart tissue from failing hearts relative to hypertrophic and healthy heart tissue, respectively. The microarray study revealed that the onset of heart failure was accompanied by a strong up-regulation of cardiac lipid metabolism genes involved in fat synthesis, storage and oxidation.