Zebrafish models for human gene regulation and disease
In recent years, zebrafish (Danio rerio) has emerged as a new vertebrate model organism for biomedical research. It offers a unique combination of traits, namely a short generation time, small size and efficient breeding procedures. Collectively, these features render it ideal for forward genetic screening studies and small-molecule screens, including toxicology. Furthermore, the transparent embryo and larvae offer unique opportunities for imaging cell movement and gene expression in a developing organism. The EU-funded ZF-HEALTH (Zebrafish regulomics for human health) project set out to perform high-throughput phenotyping of regulatory genes relevant to human disease. Towards this goal, the consortium built on technologies and concepts developed in the preceding ZF-MODELS project. Using TILLING technology, they identified 43 098 knock-out alleles in 16 096 genes and performed morphological and behavioural phenotyping for 2 569 genes. This led to the identification of over 200 abnormal phenotypes, which were further associated with specific transcriptional and behavioural profiles. Additionally, researchers characterised enhancer elements of human disease genes and using bioinformatics they detected highly conserved non-coding elements. Another significant contribution of the project was advancing the interactive Zebrafish brain atlas with brain gene expression data and images. Furthermore, through small molecule screens, the consortium identified several compounds that could be exploited in human disorders such as attention deficit, epithelial cancer and polycystic kidney disease. In addition to advancing our fundamental knowledge on key developmental processes, the ZF-HEALTH study deliverables are also disease models of great value for clinical medicine. The functional characterisation of enhancer elements will help to interpret data on human genetic variability, while the identified small molecules could serve as drug candidates.
Keywords
Zebrafish, gene regulation, ZF-HEALTH, enhancer element, small-molecule screen
