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

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

doi:10.1038/s41467-018-03476-6

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.

Highlights

Mutational inactivation of the SWI/SNF chromatin regulator ATRX occurs frequently in gliomas, the most common primary brain tumors
Recent work suggests that the deleterious effects of ATRX deficiency on genomic integrity induce the alternative lengthening of telomeres (ALT) phenotype exhibited by tumors harboring ATRX mutations[9,10]
Proliferation was reduced in the Tp53+/+ context, in accordance with prior studies showing that isolated Atrx deficiency promotes p53-dependent apoptosis[8,20,21,22]

Summary

Introduction

Mutational inactivation of the SWI/SNF chromatin regulator ATRX occurs frequently in gliomas, the most common primary brain tumors. The most common primary brain tumors, feature loss-of function mutations in the SWI/SNF chromatin remodeler gene ATRX (α-thalassemia mental retardation X-linked) as defining molecular alterations delineating major adult and pediatric disease subtypes[2,3,4,5]. These incurable glioma variants tend to exhibit morphological and immunohistochemical features of astrocytes and, are classified as “astrocytomas”. Whether and how the epigenomic consequences of ATRX deficiency promote gliomagenesis and disease-relevant phenotypes has not been explored

Methods

Results

Conclusion