ID #525 Computational analysis of aberrant gene regulation in pediatric atypical teratoid/rhabdoid tumors

Abstract

Atypical teratoid/rhabdoid (AT/RT) tumors are highly aggressive and malignant central nervous system tumors characterized by mutation and inactivation of the genes SMARCB1, or rarely SMARCA4, encoding a key subunit of the SWI/SNF chromatin remodeling complex. Despite their relatively simple mutational landscape, the epigenetic mechanisms underlying AT/RT pathogenesis remain poorly understood. During normal development, the SWI/SNF subunit composition changes during cell differentiation, and the loss of SMARCB1 may disrupt the differentiation process. In particular, the timing of SMARCB1 loss during differentiation influences the differentiation outcome. To address this temporal problem, we established an in vitro model using four AT/RT cell lines representing the SHH and MYC subtypes and simulated neuronal differentiation. To capture SMARCB1 loss-associated epigenetic and subsequent transcriptomic changes, we generate single-cell chromatin accessibility and gene expression data from each ATRT line across time points of differentiation, leveraging Single-cell Ultra-high-throughput Multiomic sequencing (SUM-seq). With this, we aim to define gene regulatory mechanisms (TF-regulatory element-gene connections) that are activated or repressed due to SMARCB1 loss and driving AT/RT cell states.