TAZ-CAMTA1 and YAP-TFE3 alter the TAZ/YAP transcriptome by recruiting the ATAC histone acetyltransferase complex
Epithelioid hemangioendothelioma (EHE) is a vascular sarcoma that metastasizes early in its clinical course 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 scr...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2021-04-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/62857 |
| _version_ | 1811236848951885824 |
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| author | Nicole Merritt Keith Garcia Dushyandi Rajendran Zhen-Yuan Lin Xiaomeng Zhang Katrina A Mitchell Nicholas Borcherding Colleen Fullenkamp Michael S Chimenti Anne-Claude Gingras Kieran F Harvey Munir R Tanas |
| author_facet | Nicole Merritt Keith Garcia Dushyandi Rajendran Zhen-Yuan Lin Xiaomeng Zhang Katrina A Mitchell Nicholas Borcherding Colleen Fullenkamp Michael S Chimenti Anne-Claude Gingras Kieran F Harvey Munir R Tanas |
| author_sort | Nicole Merritt |
| collection | DOAJ |
| description | Epithelioid hemangioendothelioma (EHE) is a vascular sarcoma that metastasizes early in its clinical course 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 in human cell lines identified YEATS2 and ZZZ3, components of the Ada2a-containing histone acetyltransferase (ATAC) complex, as key interactors of both fusion proteins despite the dissimilarity of the C terminal fusion partners CAMTA1 and TFE3. Integrative next-generation sequencing approaches in human and murine cell lines showed that the fusion proteins drive a unique transcriptome 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 fusion proteins indicates that it is a key oncogenic driver and unifying enzymatic therapeutic target for this sarcoma. This study presents an approach to mechanistically dissect how chimeric transcription factors drive the formation of human cancers. |
| first_indexed | 2024-04-12T12:15:09Z |
| format | Article |
| id | doaj.art-f5236ab6208a49dc9d2f318dd8878eee |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T12:15:09Z |
| publishDate | 2021-04-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-f5236ab6208a49dc9d2f318dd8878eee2022-12-22T03:33:27ZengeLife Sciences Publications LtdeLife2050-084X2021-04-011010.7554/eLife.62857TAZ-CAMTA1 and YAP-TFE3 alter the TAZ/YAP transcriptome by recruiting the ATAC histone acetyltransferase complexNicole Merritt0Keith Garcia1https://orcid.org/0000-0002-6078-5159Dushyandi Rajendran2Zhen-Yuan Lin3Xiaomeng Zhang4Katrina A Mitchell5Nicholas Borcherding6Colleen Fullenkamp7Michael S Chimenti8Anne-Claude Gingras9https://orcid.org/0000-0002-6090-4437Kieran F Harvey10Munir R Tanas11https://orcid.org/0000-0002-6779-2642Department of Pathology, University of Iowa, Iowa City, United StatesDepartment of Pathology, University of Iowa, Iowa City, United States; Cancer Biology Graduate Program, University of Iowa, Iowa City, United StatesLunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, United StatesLunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, United StatesPeter MacCallum Cancer Centre, Melbourne, AustraliaPeter MacCallum Cancer Centre, Melbourne, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, AustraliaDepartment of Pathology and Immunology, Washington University, St. Louis, United StatesDepartment of Pathology, University of Iowa, Iowa City, United StatesIowa Institute of Human Genetics, Carver College of Medicine, University of Iowa, Iowa City, United StatesLunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, United StatesPeter MacCallum Cancer Centre, Melbourne, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia; Department of Anatomy and Developmental Biology and Biomedicine Discovery Institute, Monash University, Clayton, AustraliaDepartment of Pathology, University of Iowa, Iowa City, United States; Cancer Biology Graduate Program, University of Iowa, Iowa City, United States; Holden Comprehensive Cancer Center, University of Iowa, Iowa City, United States; Pathology and Laboratory Medicine, Veterans Affairs Medical Center, Iowa City, United StatesEpithelioid hemangioendothelioma (EHE) is a vascular sarcoma that metastasizes early in its clinical course 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 in human cell lines identified YEATS2 and ZZZ3, components of the Ada2a-containing histone acetyltransferase (ATAC) complex, as key interactors of both fusion proteins despite the dissimilarity of the C terminal fusion partners CAMTA1 and TFE3. Integrative next-generation sequencing approaches in human and murine cell lines showed that the fusion proteins drive a unique transcriptome 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 fusion proteins indicates that it is a key oncogenic driver and unifying enzymatic therapeutic target for this sarcoma. This study presents an approach to mechanistically dissect how chimeric transcription factors drive the formation of human cancers.https://elifesciences.org/articles/62857hippo pathwaysarcomaschimeric transcription factorsfusion proteinsepigeneticsATAC complex |
| spellingShingle | Nicole Merritt Keith Garcia Dushyandi Rajendran Zhen-Yuan Lin Xiaomeng Zhang Katrina A Mitchell Nicholas Borcherding Colleen Fullenkamp Michael S Chimenti Anne-Claude Gingras Kieran F Harvey Munir R Tanas TAZ-CAMTA1 and YAP-TFE3 alter the TAZ/YAP transcriptome by recruiting the ATAC histone acetyltransferase complex eLife hippo pathway sarcomas chimeric transcription factors fusion proteins epigenetics ATAC complex |
| title | TAZ-CAMTA1 and YAP-TFE3 alter the TAZ/YAP transcriptome by recruiting the ATAC histone acetyltransferase complex |
| title_full | TAZ-CAMTA1 and YAP-TFE3 alter the TAZ/YAP transcriptome by recruiting the ATAC histone acetyltransferase complex |
| title_fullStr | TAZ-CAMTA1 and YAP-TFE3 alter the TAZ/YAP transcriptome by recruiting the ATAC histone acetyltransferase complex |
| title_full_unstemmed | TAZ-CAMTA1 and YAP-TFE3 alter the TAZ/YAP transcriptome by recruiting the ATAC histone acetyltransferase complex |
| title_short | TAZ-CAMTA1 and YAP-TFE3 alter the TAZ/YAP transcriptome by recruiting the ATAC histone acetyltransferase complex |
| title_sort | taz camta1 and yap tfe3 alter the taz yap transcriptome by recruiting the atac histone acetyltransferase complex |
| topic | hippo pathway sarcomas chimeric transcription factors fusion proteins epigenetics ATAC complex |
| url | https://elifesciences.org/articles/62857 |
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