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Pré-Publication, Document De Travail Année : 2021

Divergent transcriptional and transforming properties of PAX3-FOXO1 and PAX7-FOXO1 paralogs

Line Manceau
Julien Richard Albert
Pier-Luigi Lollini
Maxim Greenberg
Pascale Gilardi-Hebenstreit
Vanessa Ribes

Résumé

Abstract The hallmarks of the alveolar subclass of rhabdomyosarcoma are chromosomal translocations that generate chimeric PAX3-FOXO1 or PAX7-FOXO1 transcription factors. Both PAX-FOXO1s result in related cell transformation in animal models, but both mutations are associated with distinct pathological manifestations in patients. To assess the mechanisms underlying these differences, we generated isogenic fibroblast lines expressing either PAX-FOXO1 paralog. Mapping of their genomic recruitment using CUT&Tag revealed that the two chimeric proteins have distinct DNA binding preferences. In addition, PAX7-FOXO1 causes stronger de novo transactivation of its bound regions than PAX3-FOXO1, resulting in greater transcriptomic dynamics involving genes regulating cell shape and cycle. Consistently, PAX3-FOXO1 accentuates fibroblast cellular traits associated with contractility and surface adhesion and limits entry into M phase. In contrast, PAX7-FOXO1 drives cells to adopt an amoeboid shape, reduces entry into S phase, and causes more genomic instabilities. Altogether, our results argue that the diversity of rhabdomyosarcoma manifestation arises, in part, from the divergence between the transcriptional activities of PAX3-FOXO1 and PAX7-FOXO1. Furthermore, the identified pronounced deleterious effects of PAX7-FOXO1 provide an explanation for the low frequency of the translocation generating this factor in patients with rhabdomyosarcoma.

Dates et versions

hal-03438979 , version 1 (22-11-2021)

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Citer

Line Manceau, Julien Richard Albert, Pier-Luigi Lollini, Maxim Greenberg, Pascale Gilardi-Hebenstreit, et al.. Divergent transcriptional and transforming properties of PAX3-FOXO1 and PAX7-FOXO1 paralogs. 2021. ⟨hal-03438979⟩
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