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Title

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

AuthorsVicente-García, Cristina; Villarejo-Balcells, Bárbara; Irastorza-Azcárate, Ibai; Naranjo, Silvia CSIC ORCID; Acemel, Rafael D.; Tena, Juan J. CSIC ORCID; Rigby, Peter W. J.; Devos, Damien P.; Gómez-Skarmeta, José Luis CSIC ORCID ; Carvajal, Jaime J. CSIC ORCID
KeywordsTAD
CTCF
Transcriptional regulation
FOXO1
PAX3
Alveolar rhabdomyosarcoma
4C-seq
Issue Date14-Jun-2017
PublisherBioMed Central
CitationGenome Biology 18(1): 106 (2017)
Abstract[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.
Publisher version (URL)http://dx.doi.org/10.1186/s13059-017-1225-z
URIhttp://hdl.handle.net/10261/151582
DOI10.1186/s13059-017-1225-z
ISSN1474-760X
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