BPTF cooperates with MYCN/MYC to link neuroblastoma cell cycle control with epigenetic cell states [Cut&Run]

The nucleosome remodeling factor BPTF is required for the deployment of the MYC-driven transcriptional program. Deletion of oneBptfallele delays tumor progression in mouse models of pancreatic cancer and lymphoma. In neuroblastoma, MYCN cooperates with the transcriptional core regulatory circuitry (CRC). HighBPTFlevels are associated with high-risk features and decreased survival. BPTFdepletion results in a dramatic decrease of cell proliferation. Bulk RNA-seq, single-cell sequencing, and tissue microarrays reveal a positive correlation ofBPTFand CRCtranscription factor expression. Immunoprecipitation/mass spectrometry shows that BPTF interacts with MYCN and the CRC. Genome-wide distribution analysis of BPTF and CRC in neuroblastoma reveals a dual role forBPTF: 1) it co-localizes with MYCN/MYC at the promoter of genes involved in cell cycle and 2) it co-localizes withthe CRC at super-enhancers to regulate cell identity. The critical role of BPTF across neuroblastoma subtypes supports its relevance as a therapeutic target. Analysis of the genome wide distribution of BPTF assessed using Cut&Run in neuroblastoma cell lines. To further address the relevance of BPTF to neuroblastoma cell identity,we used the inducible PRRX1-mediated ADRN-MES transdifferentiation model in KP-N-YN cells.