Atrx inactivation drives disease-defining phenotypes in glioma cells of origin through global epigenomic remodeling Journal Article
| Authors: | Danussi, C.; Bose, P.; Parthasarathy, P. T.; Silberman, P. C.; Van Arnam, J. S.; Vitucci, M.; Tang, O. Y.; Heguy, A.; Wang, Y.; Chan, T. A.; Riggins, G. J.; Sulman, E. P.; Lang, F. F.; Creighton, C. J.; Deneen, B.; Miller, C. R.; Picketts, D. J.; Kannan, K.; Huse, J. T. |
| Article Title: | Atrx inactivation drives disease-defining phenotypes in glioma cells of origin through global epigenomic remodeling |
| Abstract: | Mutational inactivation of the SWI/SNF chromatin regulator ATRX occurs frequently in gliomas, the most common primary brain tumors. Whether and how ATRX deficiency promotes oncogenesis by epigenomic dysregulation remains unclear, despite its recent implication in both genomic instability and telomere dysfunction. Here we report that Atrx loss recapitulates characteristic disease phenotypes and molecular features in putative glioma cells of origin, inducing cellular motility although also shifting differentiation state and potential toward an astrocytic rather than neuronal histiogenic profile. Moreover, Atrx deficiency drives widespread shifts in chromatin accessibility, histone composition, and transcription in a distribution almost entirely restricted to genomic sites normally bound by the protein. Finally, direct gene targets of Atrx that mediate specific Atrx-deficient phenotypes in vitro exhibit similarly selective misexpression in ATRX-mutant human gliomas. These findings demonstrate that ATRX deficiency and its epigenomic sequelae are sufficient to induce disease-defining oncogenic phenotypes in appropriate cellular and molecular contexts. © 2018 The Author(s). |
| Keywords: | mutation; phenotype; molecular analysis; genomics; tumor; differentiation; cell |
| Journal Title: | Nature Communications |
| Volume: | 9 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2018-03-01 |
| Start Page: | 1057 |
| Language: | English |
| DOI: | 10.1038/s41467-018-03476-6 |
| PROVIDER: | scopus |
| PMCID: | PMC5849741 |
| PUBMED: | 29535300 |
| DOI/URL: | |
| Notes: | Article -- Erratum issued, see DOI: 10.1038/s41467-021-27820-5 -- Export Date: 1 May 2018 -- Source: Scopus |
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