Genetics of heart development
Development of any living organism is complex and genes work in vast networks to initiate the formation of proteins. The 'Definition of a genetic network involved in congenital heart disease' (CARDIOGENET) project has investigated the effects of a faulty T-box transcription factor (Tbx1) gene on heart development.A change in the Tbx1 gene causes the loss or deletion of a certain part of chromosome 22 and DiGeorge syndrome. Symptoms of this disease include heart disease as well as delay in speech development and cleft palate. By studying the effects of the Tbx1 gene on gene networks, scientists can construct a global picture of all the interacting genes involved in CHD.CARDIOGENET team members formulated new approaches for data analysis. Candidate genes were identified and confirmed in live human tissue culture (in vitro) and in mouse models. Mouse model data was successfully merged with patients' data to clarify the role of different RNA molecules and other proteins involved with gene Tbx1. CARDIOGENET scientists also generated advanced datasets for mouse RNA networks. These included molecular interaction at all levels, including changes that do not involve alterations to the DNA (epigenetic modifications) and mechanisms that occur after transcription. Transcription is an important first step in gene expression where DNA is copied into RNA.A new perspective on heart development was highlighted by the study of how transcription factors work together. For example, histone modifications in the DNA and microRNAs affect the outcome of a combination of four transcription factors that bind to the DNA.CARDIOGENET work has underlined the importance of genes and transcription factors for heart development. As well as an understanding of the disease itself, it is crucial for predicting long-term health of CHD patients.Project results have provided the scientific community with 'heart-validated' genes to screen for gene mutations in CHD patients. These genes can provide the basis for diagnosis, preventative tools and effective genetic counselling. As the underlying genetic causes of CHD may also bring about developmental problems in other organs and systems, CARDIOGENET research forms the basis of a holistic approach to tackling genetic diseases.
Keywords
Congenital heart disease, development, Tbx1, gene network, transcription
