4D Genome Architecture in Disease Associated Mutations
We are interested in disease mechanisms induced by alterations in the 3D chromatin conformation of the genome. So far, the non-coding genome has not been the focus of human genetics and Mendelian disease research on non-coding variants is only slowly emerging. This is mainly due to a large number of variants per genome and difficulties in interpreting non-coding variants. Together, this poses major problems that partially require the use of other/new technologies as well as new concepts of thinking and data interpretation. Our lab focuses on elucidating the pathomechanisms underlying disease-causing mutations in the non-coding genome.
We recently showed that deletions, duplications, inversions, translocations and insertions, collectively called structural variations (SVs) can result in disease-causing re-wiring of enhancer-promoter contacts by changing the regulatory architecture of the locus. In particular, we are investigating the effect of SVs on TAD configuration and gene expression during development.
Since there is currently no general concept to interpret mutations in the non-coding genome for their ability to cause disease, it is the aim of our group to develop such a framework and predict the regulatory effect of SVs in a disease setting.
The strength of our research lies in the tight interplay between our focus on basic research in gene regulation and the screening of large patient cohorts with limb malformations via array-CGH and whole genome sequencing. Using these methods we have identified a series of structural variations involving Conserved Non-coding Elements (CNEs) that are located in the vicinity of developmentally important genes. This includes deletions, duplications, and inversions at the BMP2 (brachydactyly type A2), SHH (mirror-image polydactyly), SOX9 (Cooks syndrome), IHH (craniosynostosis with syndactyly), MSX2 (cleidocranial dysplasia), and PITX1 (Liebenberg Syndrome) loci. Collectively, our research emphasises the role of altered gene regulation caused by structural variations as a disease-causing mechanism for a variety of Mendelian diseases.