Heart development — Role of heredity and epigenetics
Members of the 'Gene- environment interactions in heart development' (CHEARTED) project collected several clinical samples from CVM patients also presenting with Tetralogy of Fallot (TOF) and from their parents as well as normal patients for genetic epidemiology studies. Analysis of genome-wide single-nucleotide polymorphisms (SNPs) data revealed several genes associated with TOF. In diabetic pregnancy mouse models, CVM was successfully induced only when the diabetic mothers' diet was comprised of low anti-oxidants, high fat and low micro-minerals. Serial analysis of gene expression (SAGE) was carried out using next-generation SOLiD5 sequencing for microRNA expression profiling. Results revealed several differentially expressed genes and pathways associated with CVM in the diabetic embryo cases. Studies in mouse models of outflow tract defects found associations between CVMs and certain gene pathways and transcription factors such as insulin gene enhancer (ISL1). Studies on the HL1 cardiomyocyte cell line using the DamID technique revealed genes associated with cardiac transcription factors such as NKX2-5, ISL1, SRF, ELK1, ELK4 and their mutant forms. NKX2-5 and particularly the ELK proteins were found to be critical in the cardiac gene regulatory network. CHEARTED researchers developed gene prioritisation bioinformatics tools such as Endeavour to combine gene sequence and expression data from human and mouse studies with morphology and literature. Along with an open access Wiki-based database, this helped in gene prioritisation based on their functional interactions and association with congenital heart defects (CHDs). This CHD Wiki provides information on 79 syndromic genes with 274 associations between these genes and CVMs. Additionally, an online text-mining tool called Beegle was developed to search for CVM-specific data. Scientists also developed a Cardiogenetic Morphology Database (CMD) using a 3D reconstruction of heart development, gene expression patterns and genetically annotated cardiac compartments. For image reconstruction, high-resolution episcopic microscopy (HREM) images of the embryonic mouse heart at different development stages were used. Project outcomes were disseminated via the project website , publications in journals, brochures, eight news bulletins and the CMD. The project's tools, databases, models and genomic studies provide unprecedented insight into CHDs (e.g. TOF) and causative environmental factors.
