Servicenavigation

Detailseite

Zurück

Projekt Druckansicht

3D Genomarchitektur bei angeborenen Fehlbildungen

Fachliche Zuordnung Humangenetik
Förderung Förderung von 2018 bis 2023
Projektkennung Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 398111690
 
Erstellungsjahr 2023

Zusammenfassung der Projektergebnisse

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.

Projektbezogene Publikationen (Auswahl)

 
 

Zusatzinformationen

© 2025 DFG Kontakt / Impressum / Datenschutz

Textvergrößerung und Kontrastanpassung