Divergent transcriptional and transforming properties of PAX3-FOXO1 and PAX7-FOXO1 paralogs
| Autor: | Julien Richard Albert, Maxim V. C. Greenberg, Vanessa Ribes, Pascale Gilardi-Hebenstreit, Line Manceau, Pier Luigi Lollini |
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| Přispěvatelé: | Institut Jacques Monod (IJM (UMR_7592)), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Line MANCEAU, Julien RICHARD ALBERT, Pier-Luigi LOLLINI, Maxim V. C. GREENBERG, Pascale GILARDI-HEBENSTREIT1, Vanessa RIBES |
| Rok vydání: | 2021 |
| Předmět: |
endocrine system
Cancer Research Oncogene Proteins Fusion Translocation FOXO1 Chromosomal translocation Biology Cell Line Transcriptome 03 medical and health sciences Transactivation 0302 clinical medicine Rhabdomyosarcoma Genetics Animals Humans Paired Box Transcription Factors [SDV.BDD]Life Sciences [q-bio]/Development Biology Gene Transcription factor Molecular Biology PAX3 Transcription Factor Genetics (clinical) Ecology Evolution Behavior and Systematics Rhabdomyosarcoma Alveolar 030304 developmental biology 0303 health sciences PAX3 Forkhead Box Protein O1 nutritional and metabolic diseases food and beverages PAX7 Transcription Factor Forkhead Transcription Factors Fibroblasts musculoskeletal system Fusion protein PAX7 Cell biology Cell Transformation Neoplastic 030220 oncology & carcinogenesis hormones hormone substitutes and hormone antagonists |
| Zdroj: | PLoS genetics. 18(5) |
| ISSN: | 1553-7404 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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