Abstract PR002: A Genome-Derived Non-Coding Cell State Reporter Guides Therapeutic Strategies for Transcriptional Reprogramming in Neuroblastoma

Abstract

Sequential changes in transcriptional cell state are essential for normal development and are coopted in cancer. Controlling these changes for therapeutic benefit has been challenged by a lack of tools reflecting distinct states in live cells. Here, using the pediatric solid tumor high-risk neuroblastoma, which displays cellular plasticity in two main and well-characterized transcriptional states, we developed a new reporter method termed “TRECS.” TRECS integrates epigenomic and transcriptomic measurements to define endogenous genomic elements that dynamically label specific cell states in live cells, in real time. Using TRECS, we identify a chemoresistant, mesenchymal-like state controlled by the master transcription factor FOSL1 and demonstrate plasticity of cell states that show distinct sensitivities to conventional chemotherapies. Further, coupling with high-content imaging-based small molecule screens, we discover a critical role for the histone acetyltransferases EP300 and CBP in maintaining the chemoresistant cell state. Capitalizing on this, we demonstrate mechanistic rewiring of enhancer-based transcription with transient inhibition of EP300 and CBP, resulting in enhanced sensitivity to multiple chemotherapeutic agents. These results establish a genome-based mechanism to dynamically read out and perturb cell state, thereby nominating a strategy to enforce cell state changes for therapeutic benefit.