A comprehensive enhancer screen identifies TRAM2 as a key and novel mediator of YAP oncogenesis

L Li, AP Ugalde, C Scheele, SM Dieter, R van der Nagel, J Ma, A Pataskar, G Korkmaz, R Elkon, Miao Chien, Li You, Pin-Rui Su, OB (Onno) Bleijerveld, M Altelaar, L Momchev, Z Manber, R Q Han, P C van Breugel, R (Rui Filipe Marques) Lopes, P ten DijkeJ van Rheenen, Reuven Agami

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Background: Frequent activation of the co-transcriptional factor YAP is observed in a large number of solid tumors. Activated YAP associates with enhancer loci via TEAD4-DNA-binding protein and stimulates cancer aggressiveness. Although thousands of YAP/TEAD4 binding-sites are annotated, their functional importance is unknown. Here, we aim at further identification of enhancer elements that are required for YAP functions. Results: We first apply genome-wide ChIP profiling of YAP to systematically identify enhancers that are bound by YAP/TEAD4. Next, we implement a genetic approach to uncover functions of YAP/TEAD4-associated enhancers, demonstrate its robustness, and use it to reveal a network of enhancers required for YAP-mediated proliferation. We focus on EnhancerTRAM2, as its target gene TRAM2 shows the strongest expression-correlation with YAP activity in nearly all tumor types. Interestingly, TRAM2 phenocopies the YAP-induced cell proliferation, migration, and invasion phenotypes and correlates with poor patient survival. Mechanistically, we identify FSTL-1 as a major direct client of TRAM2 that is involved in these phenotypes. Thus, TRAM2 is a key novel mediator of YAP-induced oncogenic proliferation and cellular invasiveness. Conclusions: YAP is a transcription co-factor that binds to thousands of enhancer loci and stimulates tumor aggressiveness. Using unbiased functional approaches, we dissect YAP enhancer network and characterize TRAM2 as a novel mediator of cellular proliferation, migration, and invasion. Our findings elucidate how YAP induces cancer aggressiveness and may assist diagnosis of cancer metastasis.

Original languageEnglish
Article number54
JournalGenome Biology
Issue number1
Publication statusPublished - 29 Jan 2021

Bibliographical note

Funding Information:
R.A. is supported by the Dutch Science Organization (NWO-TOP), Dutch cancer society (KWF projects 10315, 11037 and 11574), and the European research council (ERC-AdG #832844). SMD was supported by a scholarship from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation; project number 415497046).

Publisher Copyright:
© 2021, The Author(s).

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