Atrx inactivation drives disease-defining phenotypes in glioma cells of origin through global epigenomic remodeling

Carla Danussi, Promita Bose, Prasanna T. Parthasarathy, Pedro C. Silberman, John S. Van Arnam, Mark Vitucci, Oliver Y. Tang, Adriana Heguy, Yuxiang Wang, Timothy A. Chan, Gregory J Riggins, Erik P. Sulman, Frederick Lang, Chad J. Creighton, Benjamin Deneen, C. Ryan Miller, David J. Picketts, Kasthuri Kannan, Jason T. Huse

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number1057
JournalNature Communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

Fingerprint

phenotype
Epigenomics
Glioma
deactivation
Chromatin
chromatin
Phenotype
Transcription
cells
telomeres
Histones
Tumors
Brain
locomotion
Genes
Genomic Instability
regulators
Telomere
Brain Neoplasms
genes

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Danussi, C., Bose, P., Parthasarathy, P. T., Silberman, P. C., Van Arnam, J. S., Vitucci, M., ... Huse, J. T. (2018). Atrx inactivation drives disease-defining phenotypes in glioma cells of origin through global epigenomic remodeling. Nature Communications, 9(1), [1057]. https://doi.org/10.1038/s41467-018-03476-6

Atrx inactivation drives disease-defining phenotypes in glioma cells of origin through global epigenomic remodeling. / Danussi, Carla; Bose, Promita; Parthasarathy, Prasanna T.; Silberman, Pedro C.; Van Arnam, John S.; Vitucci, Mark; Tang, Oliver Y.; Heguy, Adriana; Wang, Yuxiang; Chan, Timothy A.; Riggins, Gregory J; Sulman, Erik P.; Lang, Frederick; Creighton, Chad J.; Deneen, Benjamin; Miller, C. Ryan; Picketts, David J.; Kannan, Kasthuri; Huse, Jason T.

In: Nature Communications, Vol. 9, No. 1, 1057, 01.12.2018.

Research output: Contribution to journalArticle

Danussi, C, Bose, P, Parthasarathy, PT, Silberman, PC, Van Arnam, JS, Vitucci, M, Tang, OY, Heguy, A, Wang, Y, Chan, TA, Riggins, GJ, Sulman, EP, Lang, F, Creighton, CJ, Deneen, B, Miller, CR, Picketts, DJ, Kannan, K & Huse, JT 2018, 'Atrx inactivation drives disease-defining phenotypes in glioma cells of origin through global epigenomic remodeling', Nature Communications, vol. 9, no. 1, 1057. https://doi.org/10.1038/s41467-018-03476-6
Danussi, Carla ; Bose, Promita ; Parthasarathy, Prasanna T. ; Silberman, Pedro C. ; Van Arnam, John S. ; Vitucci, Mark ; Tang, Oliver Y. ; Heguy, Adriana ; Wang, Yuxiang ; Chan, Timothy A. ; Riggins, Gregory J ; Sulman, Erik P. ; Lang, Frederick ; Creighton, Chad J. ; Deneen, Benjamin ; Miller, C. Ryan ; Picketts, David J. ; Kannan, Kasthuri ; Huse, Jason T. / Atrx inactivation drives disease-defining phenotypes in glioma cells of origin through global epigenomic remodeling. In: Nature Communications. 2018 ; Vol. 9, No. 1.
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