TY - JOUR TI - Global and context-specific transcriptional consequences of oncogenic Fbw7 mutations AU - Thirimanne, H Nayanga AU - Wu, Feinan AU - Janssens, Derek H AU - Swanger, Jherek AU - Diab, Ahmed AU - Feldman, Heather M AU - Amezquita, Robert A AU - Gottardo, Raphael AU - Paddison, Patrick J AU - Henikoff, Steven AU - Clurman, Bruce E A2 - Harper, Wade A2 - White, Richard M VL - 11 PY - 2022 DA - 2022/02/28 SP - e74338 C1 - eLife 2022;11:e74338 DO - 10.7554/eLife.74338 UR - https://doi.org/10.7554/eLife.74338 AB - The Fbw7 ubiquitin ligase targets many proteins for proteasomal degradation, which include oncogenic transcription factors (TFs) (e.g., c-Myc, c-Jun, and Notch). Fbw7 is a tumor suppressor and tumors often contain mutations in FBXW7, the gene that encodes Fbw7. The complexity of its substrate network has obscured the mechanisms of Fbw7-associated tumorigenesis, yet this understanding is needed for developing therapies. We used an integrated approach employing RNA-Seq and high-resolution mapping (cleavage under target and release using nuclease) of histone modifications and TF occupancy (c-Jun and c-Myc) to examine the combinatorial effects of misregulated Fbw7 substrates in colorectal cancer (CRC) cells with engineered tumor-associated FBXW7 null or missense mutations. Both Fbw7 mutations caused widespread transcriptional changes associated with active chromatin and altered TF occupancy: some were common to both Fbw7 mutant cell lines, whereas others were mutation specific. We identified loci where both Jun and Myc were coregulated by Fbw7, suggesting that substrates may have synergistic effects. One coregulated gene was CIITA, the master regulator of MHC Class II gene expression. Fbw7 loss increased MHC Class II expression and Fbw7 mutations were correlated with increased CIITA expression in TCGA colorectal tumors and cell lines, which may have immunotherapeutic implications for Fbw7-associated cancers. Analogous studies in neural stem cells in which FBXW7 had been acutely deleted closely mirrored the results in CRC cells. Gene set enrichment analyses revealed Fbw7-associated pathways that were conserved across both cell types that may reflect fundamental Fbw7 functions. These analyses provide a framework for understanding normal and neoplastic context-specific Fbw7 functions. KW - ubiquitin KW - Fbw7 KW - Myc KW - Jun KW - chromatin KW - transcription factors JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -