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 F. Lang, Chad J. Creighton, Benjamin Deneen, C. Ryan Miller, David J. Picketts, Kasthuri Kannan and Jason T. Huse ()
Additional contact information
Carla Danussi: University of Texas MD Anderson Cancer Center
Promita Bose: Memorial Sloan-Kettering Cancer Center
Prasanna T. Parthasarathy: Memorial Sloan-Kettering Cancer Center
Pedro C. Silberman: Memorial Sloan-Kettering Cancer Center
John S. Van Arnam: University of Texas MD Anderson Cancer Center
Mark Vitucci: University of North Carolina School of Medicine
Oliver Y. Tang: Memorial Sloan-Kettering Cancer Center
Adriana Heguy: New York University School of Medicine
Yuxiang Wang: Memorial Sloan-Kettering Cancer Center
Timothy A. Chan: Memorial Sloan-Kettering Cancer Center
Gregory J. Riggins: Johns Hopkins School of Medicine
Erik P. Sulman: University of Texas MD Anderson Cancer Center
Frederick F. Lang: University of Texas MD Anderson Cancer Center
Chad J. Creighton: Baylor College of Medicine
Benjamin Deneen: Baylor College of Medicine
C. Ryan Miller: University of North Carolina School of Medicine
David J. Picketts: University of Ottawa
Kasthuri Kannan: New York University School of Medicine
Jason T. Huse: University of Texas MD Anderson Cancer Center

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-03476-6

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