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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.    Electronic supplementary material  The online version of this article (doi:10.1186/s13059-017-1225-z) contains supplementary material, which is available to authorized users.

Regulatory landscape fusion in rhabdomyosarcoma through interactions between the PAX3 promoter and FOXO1 regulatory elements