Heterogeneity in chromatin states defines a disease spectrum in synovial sarcoma

Abstract

Heterogeneity in chromatin states defines a disease spectrum in synovial sarcoma Synovial sarcoma (SyS) is an aggressive soft-tissue malignancy characterized by a pathognomonic chromosomal translocation leading to the formation of the SS18-SSX fusion oncoprotein. Previous research has indicated that SS18-SSX interacts with BAF, a chromatin remodeling complex, thereby suggesting that the deregulation of chromatin architecture serves as the oncogenic driver in this tumor type. In this study, we conducted a comprehensive multi-omics analysis on 52 primary pre-treatment human SyS tumors, employing RNA-seq, whole-genome sequencing (WGS), whole-genome bisulfite sequencing (WGBS), and chromatin immunoprecipitation sequencing (ChIP-seq) for eight histone modifications. Our epigenomic analysis unveiled distinct subgroups defined by enhancer activity and an anomalous association between the repressive H2AK119Ub and H3K27me3 marks. Furthermore, we observed a remarkable level of epigenetic state heterogeneity at fusion target genes. Notably, we discovered that the presence of bivalent promoters, marked simultaneously by the repressive H3K27me3 and the activating H3K4me3 modifications, holds significant prognostic value, surpassing the predictive capacity of tumor grade in determining patient outcomes. Lastly, our investigation identified unique epigenetic characteristics specific to SyS, such as an expansion of the H3K4me3 mark, which correlates with pronounced DNA hypomethylation of promoter regions.