Cargando…

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

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 funct...

Descripción completa

Detalles Bibliográficos
Autores principales: Li, Li, Ugalde, Alejandro P., Scheele, Colinda L. G. J., Dieter, Sebastian M., Nagel, Remco, Ma, Jin, Pataskar, Abhijeet, Korkmaz, Gozde, Elkon, Ran, Chien, Miao-Ping, You, Li, Su, Pin-Rui, Bleijerveld, Onno B., Altelaar, Maarten, Momchev, Lyubomir, Manber, Zohar, Han, Ruiqi, van Breugel, Pieter C., Lopes, Rui, ten Dijke, Peter, van Rheenen, Jacco, Agami, Reuven
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845134/
https://www.ncbi.nlm.nih.gov/pubmed/33514403
http://dx.doi.org/10.1186/s13059-021-02272-8
_version_ 1783644495183609856
author Li, Li
Ugalde, Alejandro P.
Scheele, Colinda L. G. J.
Dieter, Sebastian M.
Nagel, Remco
Ma, Jin
Pataskar, Abhijeet
Korkmaz, Gozde
Elkon, Ran
Chien, Miao-Ping
You, Li
Su, Pin-Rui
Bleijerveld, Onno B.
Altelaar, Maarten
Momchev, Lyubomir
Manber, Zohar
Han, Ruiqi
van Breugel, Pieter C.
Lopes, Rui
ten Dijke, Peter
van Rheenen, Jacco
Agami, Reuven
author_facet Li, Li
Ugalde, Alejandro P.
Scheele, Colinda L. G. J.
Dieter, Sebastian M.
Nagel, Remco
Ma, Jin
Pataskar, Abhijeet
Korkmaz, Gozde
Elkon, Ran
Chien, Miao-Ping
You, Li
Su, Pin-Rui
Bleijerveld, Onno B.
Altelaar, Maarten
Momchev, Lyubomir
Manber, Zohar
Han, Ruiqi
van Breugel, Pieter C.
Lopes, Rui
ten Dijke, Peter
van Rheenen, Jacco
Agami, Reuven
author_sort Li, Li
collection PubMed
description 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 Enhancer(TRAM2), 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13059-021-02272-8.
format Online
Article
Text
id pubmed-7845134
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-78451342021-02-01 A comprehensive enhancer screen identifies TRAM2 as a key and novel mediator of YAP oncogenesis Li, Li Ugalde, Alejandro P. Scheele, Colinda L. G. J. Dieter, Sebastian M. Nagel, Remco Ma, Jin Pataskar, Abhijeet Korkmaz, Gozde Elkon, Ran Chien, Miao-Ping You, Li Su, Pin-Rui Bleijerveld, Onno B. Altelaar, Maarten Momchev, Lyubomir Manber, Zohar Han, Ruiqi van Breugel, Pieter C. Lopes, Rui ten Dijke, Peter van Rheenen, Jacco Agami, Reuven Genome Biol Research 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 Enhancer(TRAM2), 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13059-021-02272-8. BioMed Central 2021-01-29 /pmc/articles/PMC7845134/ /pubmed/33514403 http://dx.doi.org/10.1186/s13059-021-02272-8 Text en © The Author(s) 2021 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Li, Li
Ugalde, Alejandro P.
Scheele, Colinda L. G. J.
Dieter, Sebastian M.
Nagel, Remco
Ma, Jin
Pataskar, Abhijeet
Korkmaz, Gozde
Elkon, Ran
Chien, Miao-Ping
You, Li
Su, Pin-Rui
Bleijerveld, Onno B.
Altelaar, Maarten
Momchev, Lyubomir
Manber, Zohar
Han, Ruiqi
van Breugel, Pieter C.
Lopes, Rui
ten Dijke, Peter
van Rheenen, Jacco
Agami, Reuven
A comprehensive enhancer screen identifies TRAM2 as a key and novel mediator of YAP oncogenesis
title A comprehensive enhancer screen identifies TRAM2 as a key and novel mediator of YAP oncogenesis
title_full A comprehensive enhancer screen identifies TRAM2 as a key and novel mediator of YAP oncogenesis
title_fullStr A comprehensive enhancer screen identifies TRAM2 as a key and novel mediator of YAP oncogenesis
title_full_unstemmed A comprehensive enhancer screen identifies TRAM2 as a key and novel mediator of YAP oncogenesis
title_short A comprehensive enhancer screen identifies TRAM2 as a key and novel mediator of YAP oncogenesis
title_sort comprehensive enhancer screen identifies tram2 as a key and novel mediator of yap oncogenesis
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845134/
https://www.ncbi.nlm.nih.gov/pubmed/33514403
http://dx.doi.org/10.1186/s13059-021-02272-8
work_keys_str_mv AT lili acomprehensiveenhancerscreenidentifiestram2asakeyandnovelmediatorofyaponcogenesis
AT ugaldealejandrop acomprehensiveenhancerscreenidentifiestram2asakeyandnovelmediatorofyaponcogenesis
AT scheelecolindalgj acomprehensiveenhancerscreenidentifiestram2asakeyandnovelmediatorofyaponcogenesis
AT dietersebastianm acomprehensiveenhancerscreenidentifiestram2asakeyandnovelmediatorofyaponcogenesis
AT nagelremco acomprehensiveenhancerscreenidentifiestram2asakeyandnovelmediatorofyaponcogenesis
AT majin acomprehensiveenhancerscreenidentifiestram2asakeyandnovelmediatorofyaponcogenesis
AT pataskarabhijeet acomprehensiveenhancerscreenidentifiestram2asakeyandnovelmediatorofyaponcogenesis
AT korkmazgozde acomprehensiveenhancerscreenidentifiestram2asakeyandnovelmediatorofyaponcogenesis
AT elkonran acomprehensiveenhancerscreenidentifiestram2asakeyandnovelmediatorofyaponcogenesis
AT chienmiaoping acomprehensiveenhancerscreenidentifiestram2asakeyandnovelmediatorofyaponcogenesis
AT youli acomprehensiveenhancerscreenidentifiestram2asakeyandnovelmediatorofyaponcogenesis
AT supinrui acomprehensiveenhancerscreenidentifiestram2asakeyandnovelmediatorofyaponcogenesis
AT bleijerveldonnob acomprehensiveenhancerscreenidentifiestram2asakeyandnovelmediatorofyaponcogenesis
AT altelaarmaarten acomprehensiveenhancerscreenidentifiestram2asakeyandnovelmediatorofyaponcogenesis
AT momchevlyubomir acomprehensiveenhancerscreenidentifiestram2asakeyandnovelmediatorofyaponcogenesis
AT manberzohar acomprehensiveenhancerscreenidentifiestram2asakeyandnovelmediatorofyaponcogenesis
AT hanruiqi acomprehensiveenhancerscreenidentifiestram2asakeyandnovelmediatorofyaponcogenesis
AT vanbreugelpieterc acomprehensiveenhancerscreenidentifiestram2asakeyandnovelmediatorofyaponcogenesis
AT lopesrui acomprehensiveenhancerscreenidentifiestram2asakeyandnovelmediatorofyaponcogenesis
AT tendijkepeter acomprehensiveenhancerscreenidentifiestram2asakeyandnovelmediatorofyaponcogenesis
AT vanrheenenjacco acomprehensiveenhancerscreenidentifiestram2asakeyandnovelmediatorofyaponcogenesis
AT agamireuven acomprehensiveenhancerscreenidentifiestram2asakeyandnovelmediatorofyaponcogenesis
AT lili comprehensiveenhancerscreenidentifiestram2asakeyandnovelmediatorofyaponcogenesis
AT ugaldealejandrop comprehensiveenhancerscreenidentifiestram2asakeyandnovelmediatorofyaponcogenesis
AT scheelecolindalgj comprehensiveenhancerscreenidentifiestram2asakeyandnovelmediatorofyaponcogenesis
AT dietersebastianm comprehensiveenhancerscreenidentifiestram2asakeyandnovelmediatorofyaponcogenesis
AT nagelremco comprehensiveenhancerscreenidentifiestram2asakeyandnovelmediatorofyaponcogenesis
AT majin comprehensiveenhancerscreenidentifiestram2asakeyandnovelmediatorofyaponcogenesis
AT pataskarabhijeet comprehensiveenhancerscreenidentifiestram2asakeyandnovelmediatorofyaponcogenesis
AT korkmazgozde comprehensiveenhancerscreenidentifiestram2asakeyandnovelmediatorofyaponcogenesis
AT elkonran comprehensiveenhancerscreenidentifiestram2asakeyandnovelmediatorofyaponcogenesis
AT chienmiaoping comprehensiveenhancerscreenidentifiestram2asakeyandnovelmediatorofyaponcogenesis
AT youli comprehensiveenhancerscreenidentifiestram2asakeyandnovelmediatorofyaponcogenesis
AT supinrui comprehensiveenhancerscreenidentifiestram2asakeyandnovelmediatorofyaponcogenesis
AT bleijerveldonnob comprehensiveenhancerscreenidentifiestram2asakeyandnovelmediatorofyaponcogenesis
AT altelaarmaarten comprehensiveenhancerscreenidentifiestram2asakeyandnovelmediatorofyaponcogenesis
AT momchevlyubomir comprehensiveenhancerscreenidentifiestram2asakeyandnovelmediatorofyaponcogenesis
AT manberzohar comprehensiveenhancerscreenidentifiestram2asakeyandnovelmediatorofyaponcogenesis
AT hanruiqi comprehensiveenhancerscreenidentifiestram2asakeyandnovelmediatorofyaponcogenesis
AT vanbreugelpieterc comprehensiveenhancerscreenidentifiestram2asakeyandnovelmediatorofyaponcogenesis
AT lopesrui comprehensiveenhancerscreenidentifiestram2asakeyandnovelmediatorofyaponcogenesis
AT tendijkepeter comprehensiveenhancerscreenidentifiestram2asakeyandnovelmediatorofyaponcogenesis
AT vanrheenenjacco comprehensiveenhancerscreenidentifiestram2asakeyandnovelmediatorofyaponcogenesis
AT agamireuven comprehensiveenhancerscreenidentifiestram2asakeyandnovelmediatorofyaponcogenesis