BPTF cooperates with MYCN and MYC to link neuroblastoma cell cycle control to epigenetic cellular states

Author:

Felipe Irene,Martínez-de-Villarreal Jaime,Patel Khushbu,Martínez-Torrecuadrada Jorge,Grossmann Liron D.,Roncador Giovanna,Cubells Mariona,Farrell Alvin,Kendsersky Nathan,Sabroso-Lasa Sergio,Sancho-Temiño Lucía,Torres Kyabeth,Martinez Daniel,Perez Javier Muñoz,García Fernando,Pogoriler Jenny,Moreno Lucas,Maris John M.ORCID,Real Francisco X.

Abstract

AbstractThe 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. BPTF depletion results in a dramatic decrease of cell proliferation. Bulk RNA-seq, single-cell sequencing, and tissue microarrays reveal a positive correlation ofBPTFand CRC transcription factor expression. Immunoprecipitation/mass spectrometry shows that BPTF interacts with MYCN and the CRC proteins. Genome-wide distribution analysis of BPTF and CRC in neuroblastoma reveals a dual role for BPTF: 1) it co-localizes with MYCN/MYC at the promoter of genes involved in cell cycle and 2) it co-localizes with the CRC at super-enhancers to regulate cell identity. The critical role of BPTF across neuroblastoma subtypes supports its relevance as a therapeutic target.

Publisher

Cold Spring Harbor Laboratory

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