ATRX loss suppresses the type I interferon response in sarcoma cells through chromatin remodeling

Sarcomas constitute a heterogeneous group of mesenchymal cancers and are particularly common in children and adolescents, leading to significant lethality. Therefore, it is necessary to understand the underlying mechanisms by which genetic alterations promote sarcoma progression. Here, we demonstrate that loss-of-function of ATRX, a member of the SWI/SNF DNA-remodeling family, represses the interferon (IFN)-β response by inducing chromatin remodeling in sarcoma cells. We show that ATRX mutations are associated with worse prognosis and attenuate IFN-α/β response in patients with specific types of sarcomas. Using poly(I:C) as a stimulation model, we show that natural ATRX mutation or ATRX depletion via CRISPR/Cas9 or siRNA significantly suppresses the expression of IFNB1 and other cytokines in sarcoma cells. Moreover, RNA-seq data reveal that ATRX ablation globally influences the expression pattern of poly(I:C)-stimulated genes (PSGs). Through ATAC-seq, we show that ATRX loss enhance chromatin accessibility generally, which consistent with the heterochromatin modulating function of ATRX. However, a set of PSGs display a decrease of chromatin accessibility after ATRX depletion, indicating that ATRX promote the transcription of these genes through chromatin remodeling. Thus, we highlight that ATRX mutation plays critical roles in blocking Type I IFN signaling in sarcoma cells and point out the clinical importance of this effect on sarcoma treatment.