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Genome Biol. 2017 Jun 14;18(1):106. doi: 10.1186/s13059-017-1225-z.

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

Author information

1
Centro Andaluz de Biología del Desarrollo (CABD), CSIC-UPO-JA, Universidad Pablo de Olavide, Carretera de Utrera km1, 41013, Seville, Spain.
2
Division of Cancer Biology, The Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, London, SW3 6JB, UK.
3
Centro Andaluz de Biología del Desarrollo (CABD), CSIC-UPO-JA, Universidad Pablo de Olavide, Carretera de Utrera km1, 41013, Seville, Spain. j.carvajal@csic.es.

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.

KEYWORDS:

4C-seq; Alveolar rhabdomyosarcoma; CTCF; FOXO1; PAX3; TAD; Transcriptional regulation

PMID:
28615069
PMCID:
PMC5470208
DOI:
10.1186/s13059-017-1225-z
[Indexed for MEDLINE]
Free PMC Article

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