4D Genome Architecture, Gene Regulation and Developmental Diseases

Most developmentally important genes have complex and pleiotropic expression patterns. Such spatially and temporally restricted transcriptional activities are controlled by cis-regulatory elements (enhancers, promoters) that can be far away from their target gene. To date, little is known about how enhancers contact and activate and their target genes. Specifically, how the genome functions within the space of the nucleus and its dynamic context have remained elusive and are probably one of the biggest challenges in the post-genomic era.

In the last few years, the newly developed Hi-C methods have shown that the genome is partitioned in megabase scale compartments called topologically associated domains (TADs). Because TADs restrict the range of enhancer targets, enhancers usually contact genes located within these TADs, but not outside. TADs have been shown to be surprisingly stable across cells, tissues and even species, suggesting that they function as a general folding scaffold determining domains of possible interaction partners.

Using limb development as a model system, we are investigating changes in 3D genome organisation during development. To do so, we use a large variety of state-of-the-art technologies: on the one hand, we employ Chromosomal Conformation Capture technologies (4C, Hi-C), ChIP-seq, and RNA-seq to describe regulatory landscapes. On the other hand, we apply CRISPR-Cas9 genome editing to  induce various genetic re-arrangements (deletions, inversions, duplications) and study their impact on chromatin architecture, gene regulation, and limb development.