Global gene expression in adult cardiac fibroblasts transduced with cardiac transcription factor
Ontology highlight
ABSTRACT: Four transcription factors, GATA4, Hand2, MEF2C, Tbx5 (GHMT) activated cardiac gene expression in cardiac fibroblasts, suggesting that these factors are able to reprogram fibroblasts toward a cardaic cell fate. Total RNA isolated from adult cardiac fibroblasts transduced with empty retroviral vector or GHMT-retroviruses for 2, and 4 weeks.
Project description:Four transcription factors, GATA4, Hand2, MEF2C, Tbx5 (GHMT) activated cardiac gene expression in cardiac fibroblasts, suggesting that these factors are able to reprogram fibroblasts toward a cardaic cell fate.
Project description:Prolonged electrocardiographic indices reflecting myocardial impulse conduction and repolarization are risk factors for sudden cardiac death and drug-induced arrhythmia. The PR-interval, QRS-duration and QT-interval are heritable traits influenced by multiple genetic and environmental factors. The genetic underpinnings of these traits are still largely unknown. In this study, we leveraged the variability in cardiac gene expression and the variation in PR-, QRS- and QT-intervals among F2 mice harboring the cardiac sodium ion-channel mutation Scn5a-1798insD/+ derived from the 129P2-Scn5a1798insD/+ and FVB/NJ-Scn5a1798insD/+ cross, to isolate novel genes and biological pathways impacting on cardiac conduction and repolarization. Cardiac left-ventricle total RNA from 120 F2-(129P2xFVBN/J)-Scn5a-1798insD/+ mice at 12 to 14 weeks old.
Project description:Heart formation requires the fusion of bilateral cardiomyocyte populations as they move toward the embryonic midline. The bHLH transcription factor Hand2 is essential for cardiac fusion; however, the effector genes that execute this function of Hand2 are unknown. Here, we provide the first evidence for a downstream component of the Hand2 pathway that mediates cardiac morphogenesis. Although hand2 is expressed in cardiomyocytes, mosaic analysis demonstrates that hand2 plays a non-autonomous role in regulating cardiomyocyte movement. Gene expression profiles reveal heightened expression of fibronectin 1 (fn1) in hand2 mutant embryos. Reciprocally, overexpression of hand2 leads to decreased Fibronectin levels. Furthermore, reduction of fn1 function enables rescue of cardiac fusion in hand2 mutants: bilateral cardiomyocyte populations merge and exhibit improved tissue architecture, albeit without major changes in apicobasal polarity. Together, our data provide a novel example of a tissue creating a favorable environment for its morphogenesis: the Hand2 pathway establishes an appropriate environment for cardiac fusion through negative modulation of Fn1 levels. Embryos from three independent hand2 mutant (hanS6 allele) heterozyogous crosses were collected. Examination of Tg(myl7:egfp) expression allow sorting of hand2 mutant embryos from their wild-type siblings.
Project description:Med13 cardiac over-expression regulates cardiac gene expression and metabolism Hearts from Med13 alphaMHC transgenic mice and wild type littermates
Project description:Med13 cardiac over-expression regulates obesity. Liver, WAT and BAT from alphaMHC-Med13 TG mice was analyzed Liver, WAT and BAT from Med13 alphaMHC transgenic mice and wild type littermates
Project description:Reprogramming of mouse fibroblasts toward a myocardial cell fate by forced expression of cardiac transcription factors or microRNAs has recently been demonstrated. The potential clinical applicability of these findings is based on the minimal regenerative potential of the adult human heart and the limited availability of human heart tissue. An initial, but mandatory step toward clinical application of this approach is to establish conditions for conversion of adult human fibroblasts to a cardiac phenotype. Toward this goal, we sought to determine the optimal combination of factors necessary and sufficient for direct myocardial reprogramming of human fibroblasts. Here we show that four human cardiac transcription factors, including Gata4, Hand2, Tbx5, and myocardin, and two microRNAs, miR-1 and miR-133, activated cardiac marker expression in neonatal and adult human fibroblasts. After maintenance in culture for 4-11 weeks, human fibroblasts reprogrammed with these proteins and microRNAs displayed sarcomere-like structures and calcium transients, and a small subset of such cells exhibited spontaneous contractility. These phenotypic changes were accompanied by expression of a broad range of cardiac genes and suppression of non-myocyte genes. These findings indicate that human fibroblasts can be reprogrammed to cardiac-like myocytes by forced expression of cardiac transcription factors with muscle-specific microRNAs and represent a step toward possible therapeutic application of this reprogramming approach. Human foreskin fibroblasts were transduced with 5 transcription factors and total RNA was obtained 4 weeks later. total RNA was also obtained from human foreskin fibroblasts as a negative control and adult human heart tissue as a positive control. The expression level of genes in each sample was compared.
Project description:During reprogramming of fibroblasts into cardiomyocyte-like cells by overexpression of transcription factors, GATA4, Hand2, Mef2C and Tbx5 (GHMT), H3K4Me2, an active histone code, shifts from fibroblast-exclusive peaks to cardiomyocyte-exclusive peaks. Important cardiac genes are gradually marked by this active histone marker. Mouse embryonic fibroblasts (MEFs) and neonatal mouse ventricular cardiomyocytes (NMVMs) represent fibroblasts and cardiomyocytes, respectively. Chromatins harvested from MEFs infected with retroviruses carrying GHMT at day 3, day 5, day 7 post-viral infection were prepared for immunoprecipitation.
Project description:This SuperSeries is composed of the following subset Series: GSE34457: Molecular Signatures of cardiac defects in Down syndrome lymphoblastoid cell lines (congenital heart disease) GSE34458: Molecular Signatures of cardiac defects in Down syndrome lymphoblastoid cell lines (trisomy 21) Refer to individual Series
Project description:Analysis of the transcriptome of cardiac tissue from mice transgenically expressing human cardiolipin synthesis. The hypothesis tested was that cardiac specific transgenic expression of cardiolipin synthase alters myocardial lipidomic flux resulting in compensatory metabolic gene transcriptional changes that will attenuate pathological environmental and dietary insults on bioenergetics. Total RNA obtained from cardiac tissue from transgenic cardiac specific expressing human cardiolipin synthase 1 (hCLS1) mouse model at 4 months of age compared to wildtype littermates
Project description:During reprogramming of fibroblasts into cardiomyocyte-like cells by overexpression of transcription factors, GATA4, Hand2, Mef2C and Tbx5 (GHMT), H3K4Me2, an active histone code, shifts from fibroblast-exclusive peaks to cardiomyocyte-exclusive peaks. Important cardiac genes are gradually marked by this active histone marker.