Towards spatio-temporally resolved developmental cardiac gene regulatory networks in zebrafish.

Heart formation in the zebrafish involves a rapid, complex series of morphogenetic events in three-dimensional space that spans cardiac lineage specification through to chamber formation and maturation. This process is tightly orchestrated by a cardiac gene regulatory network (GRN), which ensures the precise spatio-temporal deployment of genes critical for heart formation. Alterations of the timing or spatial localisation of gene expression can have a significant impact in cardiac ontogeny and may lead to heart malformations. Hence, a better understanding of the cellular and molecular basis of congenital heart disease relies on understanding the behaviour of cardiac GRNs with precise spatiotemporal resolution. Here, we review the recent technical advances that have expanded our capacity to interrogate the cardiac GRN in zebrafish. In particular, we focus on studies utilising high-throughput technologies to systematically dissect gene expression patterns, both temporally and spatially during heart development.

Navigating the non-coding genome in heart development and Congenital Heart Disease.

Congenital Heart Disease (CHD) is characterised by a wide range of cardiac defects, from mild to life-threatening, which occur in babies worldwide. To date, there is no cure to CHD, however, progress in surgery has reduced its mortality allowing children affected by CHD to reach adulthood. In an effort to understand its genetic basis, several studies involving whole-genome sequencing (WGS) of patients with CHD have been undertaken and generated a great wealth of information. The majority of putative causative mutations identified in WGS studies fall into the non-coding part of the genome. Unfortunately, due to the lack of understanding of the function of these non-coding mutations, it is challenging to establish a causal link between the non-coding mutation and the disease. Thus, here we review the state-of-the-art approaches to interpret non-coding mutations in the context of CHD and address the following questions: What are the non-coding sequences important for cardiac function? Which technologies are used to identify them? Which resources are available to analyse them? What mutations are expected in these non-coding sequences? Learning from developmental process, what is their expected role in CHD?