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

ABSTRACT: Hallmarks of the alveolar subclass of Rhabdomyosarcoma are chromosomal translocations that generate PAX3-FOXO1 or PAX7-FOXO1 chimeric transcription factors. Both PAX-FOXO1s drive related cell transformation in animal models, yet the two mutations are associated with distinct pathological manifestations in patients. To evaluate the mechanisms underlying these differences, we generated isogenic fibroblast lines expressing either PAX-FOXO1 paralog. Mapping their genome recruitment using CUT&Tag revealed that the two chimeric proteins have distinct DNA binding preferences. Furthermore, 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 to M phase. Instead, PAX7-FOXO1 pushes cells to adopt an amoeboid-like shape, reduce S phase entry and provokes more genome instabilities. Altogether, our results demonstrate that PAX7-FOXO1 has a greater chromatin remodelling and transactivating abilities and is more deleterious to cells than PAX3-FOXO1. Altogether our results argue that the diversity in rhabdomyosarcoma manifestation stems, in part, from the diverging transcriptional activity of PAX3-FOXO1 and PAX7-FOXO1. Furthermore, PAX7-FOXO1 pronounced deleterious effects provides an explanation for the low frequency of the translocation generating this factor in Rhabdomyosarcoma patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE180919 | GEO | 2021/08/15

REPOSITORIES: GEO

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