Servicenavigation

Project Details

Back

Projekt Print View

3D Genome Architecture in Congenital Disease

Subject Area Human Genetics
Term from 2018 to 2023
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 398111690
 
Final Report Year 2023

Final Report Abstract

Overall, this project has been very successful. We were able to describe an important disease mechanism in which genomic rearrangements result in gene misexpression via the alteration of regulatory landscapes. 3D genomics contributed to a large degree to our understanding of the underlying mechanisms. Furthermore, we described a condition in which the deletion of a long noncoding RNA (lncRNA) causes disease because it is an essential and tissue-specific activator of its target gene. Further studies unraveled fundamental mechanisms of when and how rearrangements can cause gene misexpression. First, it has become clear that the genome is robust against rearrangements and that only a small subset of SVs will finally result in gene misexpression. The case selection is strongly biased to select cases that show an effect. The study of congenital chromothripsis cases has shown that there is an unexpected robustness towards rearrangements. Our study at the Sox9 locus, where we removed several CTCF sites, including the boundary, showed that enhancers contact their cognate promoters even if the 3D genome architecture is lost. Nevertheless, we observed “leakage” from one TAD to the other, which in selected cases may be sufficient to cause a phenotype. However, rearrangements that replace CTCF sites, thereby forcing enhancers on other targets, can result in gene misexpression and disease. Thus, the 3D genomics approach has important implications but does not solve all cases. In fact, only a minority of cases appear to be caused by mechanisms that involve SV-induced ectopic enhancerpromoter contacts.

Publications

 
 

Additional Information

© 2025 DFG Disclaimer / Copyright / Privacy Policy

Textvergrößerung und Kontrastanpassung