Abstract

Abstract Deficiency of ATRX (Alpha Thalassemia/Mental Retardation Syndrome X-linked), a core member of SWI/SNF family chromatin regulator is altered in diffuse gliomas and coexist with IDH1/2 mutations in adults and histone G34R/V alterations in pediatric populations. Loss of ATRX has been associated with global alterations in chromatin accessibility and epigenomics landscape, however, the detail mechanism behind the oncogenic transformation remains elusive. Integrating transcriptomics and in-depth positional epigenome analysis over repetitive DNA sequences in progenitor and tumors models of murine and human gliomas, we describe ATRX-deficient gliomas is fundamentally a disease of altered Transposable Elements (TE’s) and regulates neuronal differentiation and cell motility in gliomas, as validated pharmacologically and genetically. Epigenome assessment reported de-repression of LINE-1 (Long interspersed nuclear elements-1), specifically at Lamina-Associated Domains (LADs) with gain of enhancer histone marks, with association in chromatin loops/topology in ATRX-deficient glioma cells. Moreover, our single cell-RNA seq analysis focusing on TE’s and molecular docking studies in human glioma stem cells demonstrated LINE-1 regulates oncogenic alternative splicing events and neuro-developmental signatures. Expanding the analysis, we identified a subset of evolutionary young regulatory TE’s to play critical role in ATRX-deficient gliomas involved in neuronal differentiation phenotype. To summarize, our cross-species analysis establishes tangible links between ATRX deficiency and multiscale dysregulated 3D-epigenomic architecture that hijack regulates onco-exaptation programs in gliomas. We further discover that enhancer-like TE’s fine-tune the transcriptional program with important clinical implications, that could help in developing treatment options in malignant gliomas.