| First Author | Vicente-García C | Year | 2017 |
| Journal | Genome Biol | Volume | 18 |
| Issue | 1 | Pages | 106 |
| PubMed ID | 28615069 | Mgi Jnum | J:255066 |
| Mgi Id | MGI:6109900 | Doi | 10.1186/s13059-017-1225-z |
| Citation | Vicente-Garcia C, et al. (2017) Regulatory landscape fusion in rhabdomyosarcoma through interactions between the PAX3 promoter and FOXO1 regulatory elements. Genome Biol 18(1):106 |
| abstractText | BACKGROUND: The organisation of vertebrate genomes into topologically associating domains (TADs) is believed to facilitate the regulation of the genes located within them. A remaining question is whether TAD organisation is achieved through the interactions of the regulatory elements within them or if these interactions are favoured by the pre-existence of TADs. If the latter is true, the fusion of two independent TADs should result in the rewiring of the transcriptional landscape and the generation of ectopic contacts. RESULTS: We show that interactions within the PAX3 and FOXO1 domains are restricted to their respective TADs in normal conditions, while in a patient-derived alveolar rhabdomyosarcoma cell line, harbouring the diagnostic t(2;13)(q35;q14) translocation that brings together the PAX3 and FOXO1 genes, the PAX3 promoter interacts ectopically with FOXO1 sequences. Using a combination of 4C-seq datasets, we have modelled the three-dimensional organisation of the fused landscape in alveolar rhabdomyosarcoma. CONCLUSIONS: The chromosomal translocation that leads to alveolar rhabdomyosarcoma development generates a novel TAD that is likely to favour ectopic PAX3:FOXO1 oncogene activation in non-PAX3 territories. Rhabdomyosarcomas may therefore arise from cells which do not normally express PAX3. The borders of this novel TAD correspond to the original 5''- and 3''- borders of the PAX3 and FOXO1 TADs, respectively, suggesting that TAD organisation precedes the formation of regulatory long-range interactions. Our results demonstrate that, upon translocation, novel regulatory landscapes are formed allowing new intra-TAD interactions between the original loci involved. |
