Project description:Through genome-wide transcriptional comparisons, this study interrogates the capacity of iPSCs to accurately model pathogenic signatures of structural cardiac defects. Herein, we studied the molecular etiology of structural cardiac defects in Nos3-/- mice via transcriptional analysis of stage-matched embryonic and iPSC-derived tissues. In vitro comparisons of differentiated embryoid bodies were calibrated to in utero benchmarks of health and disease. Integrated systems biology analysis of WT and Nos3-/- transcriptional profiles revealed 50% concordant expression patterns between in utero embryonic and ex vivo iPSC-derived tissue. In particular, up-regulation of glucose metabolism (p-value = 3.95x10-12) and down-regulation of fatty acid metabolism (p-value = 6.71x10-12) highlight a bioenergetic signature of early Nos3 deficiency during cardiogenesis that can be recapitulated in iPSC-derived tissues. The in vitro concordance of early Nos3-/- disease signatures supports the utility of iPSCs as a cell-autonomous model of structural heart defects. Moreover, this study supports the use of iPSCs as a platform to pinpoint initial stages of cardiac pathogenesis.
Project description:Through genome-wide transcriptional comparisons, this study interrogates the capacity of iPSCs to accurately model pathogenic signatures of structural cardiac defects. Herein, we studied the molecular etiology of structural cardiac defects in Nos3-/- mice via transcriptional analysis of stage-matched embryonic and iPSC-derived tissues. In vitro comparisons of differentiated embryoid bodies were calibrated to in utero benchmarks of health and disease. Integrated systems biology analysis of WT and Nos3-/- transcriptional profiles revealed 50% concordant expression patterns between in utero embryonic and ex vivo iPSC-derived tissue. In particular, up-regulation of glucose metabolism (p-value = 3.95x10-12) and down-regulation of fatty acid metabolism (p-value = 6.71x10-12) highlight a bioenergetic signature of early Nos3 deficiency during cardiogenesis that can be recapitulated in iPSC-derived tissues. The in vitro concordance of early Nos3-/- disease signatures supports the utility of iPSCs as a cell-autonomous model of structural heart defects. Moreover, this study supports the use of iPSCs as a platform to pinpoint initial stages of cardiac pathogenesis.
Project description:We compared the epigenetic status of the mutant and disease-free iPSCs at the whole genome level. Whole epigenome profiling based on trimethylated H3K4 (H3K4me3) showed concordant epigenetic remodeling in the two corrected clones when compared with two mutant iPSC clones. Examination of the trimethylated H3K4 histone modification in Fanconi anemia patient iPSCs before and after gene correction
Project description:We compared the epigenetic status of the mutant and disease-free iPSCs at the whole genome level. Whole epigenome profiling based on trimethylated H3K4 (H3K4me3) showed concordant epigenetic remodeling in the two corrected clones when compared with two mutant iPSC clones. Examination of genome-wide gene expression in Fanconi anemia patient iPSCs before and after gene correction
Project description:We compared the epigenetic status of the mutant and disease-free iPSCs at the whole genome level. Whole epigenome profiling based on trimethylated H3K4 (H3K4me3) showed concordant epigenetic remodeling in the two corrected clones when compared with two mutant iPSC clones.
Project description:We compared the epigenetic status of the mutant and disease-free iPSCs at the whole genome level. Whole epigenome profiling based on trimethylated H3K4 (H3K4me3) showed concordant epigenetic remodeling in the two corrected clones when compared with two mutant iPSC clones.