The regulation of transcription plays a crucial role in animal development. It is orchestrated by enhancers, non-coding DNA elements that are bound by multiple transcription factors in a sequence-specific manner. A typical enhancer activates the expression of its target gene, often over long genomic distances, which in turn specifies the fate of different cell types during development. We will use mouse embryo development as a model system and a combination of novel genome editing (Kvon et al., 2016) and genomics tools to understand how enhancers work in the 3D genome in the context of mammalian development.
IN congenital disorders
Many human variants associated with congenital disorders are hypothesized to affect developmental enhancers. Determining which of these potentially pathogenic enhancer variants are important and understanding the etiology of the enhancer malfunction is a major challenge. We will use novel mouse transgenesis tools that are based on CRISPR/Cas9 (Kvon et al., 2020) and single-cell RNA sequencing to assess the effect of human variants on enhancer activity in vivo and to understand the mechanism by which they disrupt target gene expression that eventually leads to congenital limb malformations.
IN vertebrate evolution
Changes in gene regulatory networks are hypothesized to be a primary driver of changes in body shape between different animals, but identifying genomic loci associated with major morphological transitions in vertebrates has remained challenging. The mouse is a powerful model for studying evolution loci because regulatory DNA sequences from different vertebrate species can be introduced into the mouse genome, and their activities can be directly compared with each other (Kvon et al., 2016). We are interested in using mice to further develop novel genome manipulation tools to better understand the molecular basis of vertebrate evolution.