Mechanismen und Pathologie von Long Range Regulation während der Extremitätenentwicklung
Zusammenfassung der Projektergebnisse
Non-genic chromosomal alterations can lead to important changes in gene expression, and contribute substantially to congenital developmental defects. In the framework of this project, we have explored the underlying mechanisms, focussing on two loci involved in limb malformations. Our work shows that the segmentation of the genome in distinct topological domains plays an essential role in directing distant cis-regulatory elements to their target genes. Remodelling of these domains can alter substantially enhancerpromoter communications, leading to ectopic gene activation. The simple knowledge of the position of the different elements involved (enhancers, genes, topological boundaries) can already provide strong indications on what are the consequences of specific rearrangements. These findings are particularly important, as they allow better diagnosis of such conditions, as well as better counselling regarding the potential effects of de novo genomic rearrangements. The different mouse models we have now generated for Cooks syndromes, Pierre Robin, SHH-associated polydactylies and others, will be also particularly useful to study in details the etiology of the corresponding conditions in humans. Our work has also substantially contributed to functionally demonstrate the role of TADs in gene expression, and identify cis-acting elements that contribute to their formation. We have also uncovered the role of these domains in promoting functional interactions between elements which will otherwise be only sporadically in contact. These data showed that the 3D organisation of the genome is an integral component of the mechanisms that confer robustness and reproducibility to developmental processes, which largely rely on distant cis-regulatory interactions. Finally, we have shown that contrarily to the current models, the 3D architecture of the mammalian genome results from two independent systems, acting independently of each other. These new findings represent an important step forward in our understanding of a fundamental process in genome function.
Projektbezogene Publikationen (Auswahl)
- Two independent modes of chromatin organization are revealed by cohesin removal
Schwarzer W, et al.
- (2016). Formation of new chromatin domains determines pathogenicity of genomic duplications. Nature 538, 265–269
Franke, M., Ibrahim, D.M., Andrey, G., Schwarzer, W., Heinrich, V., Schöpflin, R., Kraft, K., Kempfer, R., Jerković, I., Chan, W.L., et al.
(Siehe online unter https://doi.org/10.1038/nature19800) - (2016). Gene regulation at a distance: From remote enhancers to 3D regulatory ensembles. Semin. Cell Dev. Biol. 57, 57–67
Spitz, F.
(Siehe online unter https://doi.org/10.1016/j.semcdb.2016.06.017) - (2016). The Shh Topological Domain Facilitates the Action of Remote Enhancers by Reducing the Effects of Genomic Distances. Dev Cell 39, 529-543
Symmons, O., Pan, L., Remeseiro, S., Aktas, T., Klein, F., Huber, W., and Spitz, F.
(Siehe online unter https://doi.org/10.1016/j.devcel.2016.10.015)
