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Genetic and epigenetic alterations in patients with congenital heart disease

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An overview of regulatory circuits establishing the cardiac transcriptome will be shown. A particular focus is the interaction between different molecular levels, involving epigenetic, transcriptional and post-transcriptional mechanisms.

Beside the study of mouse models, we apply high-throughput technology to gain insights into congenital heart disease with a particular interest on Tetralogy of Fallot (ToF). More than ten years ago we provided the first genome-wide expression profiles of normal and diseased human hearts. More recently, we showed that ToF is an oligogenetic disorder and most interestingly mutated genes are key factor of SHF differentiation, and we predict that impaired differentiation and proliferation capacity of SHF progenitors is one main impact on the dys-developed.

In addition, we just conducted a genome-wide study of DNA methylation alteration. We linked DNA methylation with genome-wide expression data and found a significant overlap for hypermethylated promoters and down-regulated genes, and vice versa. Among the differentially methylated genes with distinct expression changes are the sarcomeric component TNNI1 , the co-receptor TDGF1 , the endothelin converting enzyme ECE2 , and the cytochrome C oxidase assembly protein SCO2 . Moreover, we found examples of methylation changes co-localized with novel, differential splicing events among sarcomeric genes.

Finally, we demonstrate the interaction of differentially methylated and expressed genes in TOF with mutated CHD genes in a molecular network. In order to perform functional follow up studies, we currently apply human iPSCs technology and their differentiation to cardiomyocytes

This talk is part of the Cambridge Cardiovascular Seminar Series series.

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