Rewiring the fusion oncoprotein EWSR1::FLI1 in Ewing scarcoma with bivalent small molecules  [ATAC-seq]
Dysregulated transcription is a defining hallmark of cancer. Recently, novel chemically induced proximity approaches have enabled the rewiring of transcriptional machinery to drive expression of pro-apoptotic genes using bivalent small molecules.  In this work, we demonstrate that this strategy is amenable to relocalizing DNA bound transcriptional machinery, such as fusion transcription factors that commonly drive pediatric malignancies. Targeting fusion transcription factors, such as EWSR1::FLI1 in Ewing sarcoma, with these bivalent compounds may open new therapeutic avenues. Here, we develop a small molecule, EB-TCIP, that recruits FKBP12F36V-tagged EWSR1::FLI1 to DNA sites bound by the transcriptional regulator BCL6, leading to rapid chromatin remodeling and expression of BCL6 target genes. This proof-of-concept study demonstrates that DNA binding proteins with pioneering transcription factor activity, such as EWSR1::FLI1, can be relocalized on chromatin to induce expression of repressed genes. Insights herein will guide the development of future bivalent molecules that rewire DNA binding transcriptional machinery. Overall design: Investigate changes in chromatin accessibility after 4 hour treatment with EB-TCIP compared to DMSO, NEG-1 and NEG-2 controls (two replicates).  Under GEO GSE290893 (ATAC-Seq) 24 hour samples EB-TCIP is labelled as BAK212,