Chromothripsis entschlüsseln
Zusammenfassung der Projektergebnisse
Chromothripsis is a type of genomic instability characterized by catastrophic genome rearrangements. The mechanistic basis of chromothripsis has been mostly studied in inducible cell systems or by applying chemicals to cause chromothriptic events. Here, we used a model of spontaneous chromothripsis occurrence in primary patient-derived fibroblasts, complemented by functional assays in fibroblasts after p53 down regulation. We showed that nucleotide insufficiency induced by p53 deficiency leads to replication stress driving genomic instability. In addition, we developed assays to study chromosome instability at single-cell level and we identified pervasive subclonal chromothripsis in cancer. Finally, we discovered new types of chromosome instability that are linked with chromothripsis and we characterized the role of chromothripsis in treatment resistance.
Projektbezogene Publikationen (Auswahl)
-
Long-read sequencing of diagnosis and post-therapy medulloblastoma reveals complex rearrangement patterns and epigenetic signatures. Cell Genomics, 3(4), 100281.
Rausch, Tobias; Snajder, Rene; Leger, Adrien; Simovic, Milena; Giurgiu, Mădălina; Villacorta, Laura; Henssen, Anton G.; Fröhling, Stefan; Stegle, Oliver; Birney, Ewan; Bonder, Marc Jan; Ernst, Aurelie & Korbel, Jan O.
-
HIPSD&R-seq enables scalable genomic copy number and transcriptome profiling. Genome Biology, 25(1).
Otoničar, Jan; Lazareva, Olga; Mallm, Jan-Philipp; Simovic-Lorenz, Milena; Philippos, George; Sant, Pooja; Parekh, Urja; Hammann, Linda; Li, Albert; Yildiz, Umut; Marttinen, Mikael; Zaugg, Judith; Noh, Kyung Min; Stegle, Oliver & Ernst, Aurélie
-
Multi-omic and single-cell profiling of chromothriptic medulloblastoma reveals genomic and transcriptomic consequences of genome instability. Nature Communications, 15(1).
Smirnov, Petr; Przybilla, Moritz J.; Simovic-Lorenz, Milena; Parra, R. Gonzalo; Susak, Hana; Ratnaparkhe, Manasi; Wong, John KL.; Körber, Verena; Mallm, Jan-Philipp; Philippos, George; Sill, Martin; Kolb, Thorsten; Kumar, Rithu; Casiraghi, Nicola; Okonechnikov, Konstantin; Ghasemi, David R.; Maaß, Kendra Korinna; Pajtler, Kristian W.; Jauch, Anna ... & Ernst, Aurélie
-
Spatio-temporal transcriptomics of chromothriptic SHH-medulloblastoma identifies multiple genetic clones that resist treatment and drive relapse. Nature Communications, 15(1).
Kats, Ilia; Simovic-Lorenz, Milena; Schreiber, Hannah Sophia; Sant, Pooja; Mallm, Jan-Philipp; Körber, Verena; Li, Albert; Velmurugan, Pravin; Heuer, Sophie; Kües, Luisa; Devens, Frauke; Sill, Martin; Jugold, Manfred; Moustafa, Mahmoud; Abdollahi, Amir; Winkler, Frank; Korshunov, Andrey; Pfister, Stefan M.; Stegle, Oliver & Ernst, Aurélie
