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TAZ-CAMTA1 and YAP-TFE3 modulate the basal TAZ/YAP transcriptional program by recruiting the ATAC histone acetyltransferase complex

By Nicole Merritt, Keith Garcia, Dushyandi Rajendran, Zhen-Yuan Lin, Xiaomeng Zhang, Katrina M. Mitchell, Nicholas Borcherding, Colleen Fullenkamp, Michael Chimenti, Anne-Claude Gingras, Kieran F Harvey, Munir R. Tanas

Posted 08 Sep 2020
bioRxiv DOI: 10.1101/2020.09.07.286633

Epithelioid hemangioendothelioma (EHE) is a vascular sarcoma that metastasizes early and lacks an effective medical therapy. The TAZ-CAMTA1 and YAP-TFE3 fusion proteins are chimeric transcription factors and initiating oncogenic drivers of EHE. A combined proteomic/genetic screen identified YEATS2 and ZZZ3, components of the Ada2a-containing histone acetyltransferase (ATAC) complex, as key interactors of both TAZ-CAMTA1 and YAP-TFE3 despite the dissimilarity of the C terminal fusion partners CAMTA1 and TFE3. An integrative next generation sequencing approach showed the fusion proteins drive expression of a unique transcriptome distinct from TAZ and YAP by simultaneously hyperactivating a TEAD-based transcriptional program and modulating the chromatin environment via interaction with the ATAC complex. Interaction of the ATAC complex with both TAZ-CAMTA1 and YAP-TFE3 indicates the histone acetyltransferase complex is an oncogenic driver in EHE and potentially other sarcomas. Furthermore, the ATAC complex is an enzymatic transcriptional cofactor required for both fusion proteins in EHE, representing a unifying therapeutic target for this sarcoma. Gene fusions are the most common genetic alterations activating TAZ and YAP in cancer, and this study serves as a template for identifying epigenetic modifiers recruited by the C terminal fusion partners of other TAZ/YAP gene fusions occurring in gliomas, carcinomas, and other sarcomas. Summary TAZ-CAMTA1 and YAP-TFE3 alter the TAZ/YAP transcriptional program by recruiting the ATAC complex and modifying the chromatin landscape. ### Competing Interest Statement The authors have declared no competing interest.

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