Development and Disease Group

Introduction and scope of research

The Research Group Development & Disease focuses on the question how genomic information governs normal and abnormal embryonic development. We aim at better understanding the basic mechanisms how genes are regulated in a genomic context and how this intricate process is altered in human disease. To study the molecular cause and developmental pathology of human malformations, we focus on skeletal development, and here in particular on the limb. Limb malformatons are a relatively common type of human malformation. They are phenotypically and geneticially extremely heterogenous and while many disease gene mutations have been identified, the majority of cases remain unsolved. In our studies we focus on the function of the non-coding genome and study its role in gene regulation and disease pathology. We want to find out how genes are regulated during development and how variants in the non-coding genome can be disease causing. Our particular interest is in large genomic rearrangements, so called structural variations, and their effect on gene regualtion and the 3D architecture of our chromosomes.

Our methodology

Chromosomes are folded in the nuclues according to a specific code. This 3D structure of the chromatin directly affects the regulation of genes by facilitating and restricting the contacts regulatory elements can make. Chromosome conformations capture (3C) technologies (4C and HiC) are used by us to measure and visualize chromatin folding and how it is altered by mutations. We study the mechanisms and rules of chromatin folding in vivo in cells/tissues from mouse embryos. This allows us to be a close as possible to the developmental processes and the diseases that are of interest to us. Mutations are produced by genome editing with CRISPR/Cas9 in mouse embryonic stem (ES) cells and mice are then generated by ES cell aggregation. We use the developing limb as a model system to study how gene regulation changes and directs morphogenesis. The limb has many advantages for this sort of study as it is accessible and the developmental steps and the major genes/molecular mechanisms are known. This allows us to directly link gene regulation with basic develomental processes and phenotype. Thus, we study how 3D genomics governs 3D development. 

We analyse human genomes from individuals with malformations by Illumina and other technologies to identify disease causing variants. A range of bioinformatic tools are applied for genome analysis, 4C, HiC and other applications.

Our questions, our goals

How are genes regulated and how is this related to 3D folding of chromatin? How do enhancers work and how is their activity influenced by epigenetic modifications? And, finally, how are these processes related to diesease? Ultimately, we want to understand the cause and pathology of human abnormal development (malformations) in order to develop better diagnostic tests and/or for treatment. The effect of variants in the non-coding genome is currently difficult to predict. We want to understand mechanisms of gene regulation during development to better understand how abnormal gene regulation can result in disease. The research group works in close collaboration with the Institute for Medical and Human Genetics (IMG) at the Charité - Universitätsmedizin Berlin. The IMG provides a direct clinical connection to our work and the possibility to translate knowledge gained into clinical practice.

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