2024-03-28T15:48:22Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/1515822020-01-13T11:52:35Zcom_10261_128com_10261_1col_10261_381
Regulatory landscape fusion in rhabdomyosarcoma through interactions between the PAX3 promoter and FOXO1 regulatory elements
Vicente-García, Cristina
Villarejo-Balcells, Bárbara
Irastorza-Azcárate, Ibai
Naranjo, Silvia
Acemel, Rafael D.
Tena, Juan J.
Rigby, Peter W. J.
Devos, Damien P.
Gómez-Skarmeta, José Luis
Carvajal, Jaime J.
Cancer Research UK
Ministerio de Ciencia e Innovación (España)
European Commission
Ministerio de Economía y Competitividad (España)
Junta de Andalucía
CSIC - Unidad de Recursos de Información Científica para la Investigación (URICI)
TAD
CTCF
Transcriptional regulation
FOXO1
PAX3
Alveolar rhabdomyosarcoma
4C-seq
[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.
2017-06-18T03:18:57Z
2017-06-18T03:18:57Z
2017-06-14
2017-06-18T03:18:58Z
artículo
Genome Biology 18(1): 106 (2017)
1474-760X
http://hdl.handle.net/10261/151582
10.1186/s13059-017-1225-z
http://dx.doi.org/10.13039/501100000289
http://dx.doi.org/10.13039/501100004837
http://dx.doi.org/10.13039/501100000780
http://dx.doi.org/10.13039/501100003329
http://dx.doi.org/10.13039/501100011011
28615069
en
Publisher's version
http://dx.doi.org/10.1186/s13059-017-1225-z
Sí
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BFU2013-41322-P
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BFU2013-40866-P
http://creativecommons.org/licenses/by/4.0/
openAccess
BioMed Central