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The high mobility group protein HMG20A cooperates with the histone reader PHF14 to modulate TGFβ and Hippo pathways
High mobility group (HMG) proteins are chromatin regulators with essential functions in development, cell differentiation and cell proliferation. The protein HMG20A is predicted by the AlphaFold2 software to contain three distinct structural elements, which we have functionally characterized: i) an...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9508832/ https://www.ncbi.nlm.nih.gov/pubmed/36124662 http://dx.doi.org/10.1093/nar/gkac766 |
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author | Gómez-Marín, Elena Posavec-Marjanović, Melanija Zarzuela, Laura Basurto-Cayuela, Laura Guerrero-Martínez, José A Arribas, Gonzalo Yerbes, Rosario Ceballos-Chávez, María Rodríguez-Paredes, Manuel Tomé, Mercedes Durán, Raúl V Buschbeck, Marcus Reyes, José C |
author_facet | Gómez-Marín, Elena Posavec-Marjanović, Melanija Zarzuela, Laura Basurto-Cayuela, Laura Guerrero-Martínez, José A Arribas, Gonzalo Yerbes, Rosario Ceballos-Chávez, María Rodríguez-Paredes, Manuel Tomé, Mercedes Durán, Raúl V Buschbeck, Marcus Reyes, José C |
author_sort | Gómez-Marín, Elena |
collection | PubMed |
description | High mobility group (HMG) proteins are chromatin regulators with essential functions in development, cell differentiation and cell proliferation. The protein HMG20A is predicted by the AlphaFold2 software to contain three distinct structural elements, which we have functionally characterized: i) an amino-terminal, intrinsically disordered domain with transactivation activity; ii) an HMG box with higher binding affinity for double-stranded, four-way-junction DNA than for linear DNA; and iii) a long coiled-coil domain. Our proteomic study followed by a deletion analysis and structural modeling demonstrates that HMG20A forms a complex with the histone reader PHF14, via the establishment of a two-stranded alpha-helical coiled-coil structure. siRNA-mediated knockdown of either PHF14 or HMG20A in MDA-MB-231 cells causes similar defects in cell migration, invasion and homotypic cell–cell adhesion ability, but neither affects proliferation. Transcriptomic analyses demonstrate that PHF14 and HMG20A share a large subset of targets. We show that the PHF14-HMG20A complex modulates the Hippo pathway through a direct interaction with the TEAD1 transcription factor. PHF14 or HMG20A deficiency increases epithelial markers, including E-cadherin and the epithelial master regulator TP63 and impaired normal TGFβ-trigged epithelial-to-mesenchymal transition. Taken together, these data indicate that PHF14 and HMG20A cooperate in regulating several pathways involved in epithelial–mesenchymal plasticity. |
format | Online Article Text |
id | pubmed-9508832 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-95088322022-09-26 The high mobility group protein HMG20A cooperates with the histone reader PHF14 to modulate TGFβ and Hippo pathways Gómez-Marín, Elena Posavec-Marjanović, Melanija Zarzuela, Laura Basurto-Cayuela, Laura Guerrero-Martínez, José A Arribas, Gonzalo Yerbes, Rosario Ceballos-Chávez, María Rodríguez-Paredes, Manuel Tomé, Mercedes Durán, Raúl V Buschbeck, Marcus Reyes, José C Nucleic Acids Res Gene regulation, Chromatin and Epigenetics High mobility group (HMG) proteins are chromatin regulators with essential functions in development, cell differentiation and cell proliferation. The protein HMG20A is predicted by the AlphaFold2 software to contain three distinct structural elements, which we have functionally characterized: i) an amino-terminal, intrinsically disordered domain with transactivation activity; ii) an HMG box with higher binding affinity for double-stranded, four-way-junction DNA than for linear DNA; and iii) a long coiled-coil domain. Our proteomic study followed by a deletion analysis and structural modeling demonstrates that HMG20A forms a complex with the histone reader PHF14, via the establishment of a two-stranded alpha-helical coiled-coil structure. siRNA-mediated knockdown of either PHF14 or HMG20A in MDA-MB-231 cells causes similar defects in cell migration, invasion and homotypic cell–cell adhesion ability, but neither affects proliferation. Transcriptomic analyses demonstrate that PHF14 and HMG20A share a large subset of targets. We show that the PHF14-HMG20A complex modulates the Hippo pathway through a direct interaction with the TEAD1 transcription factor. PHF14 or HMG20A deficiency increases epithelial markers, including E-cadherin and the epithelial master regulator TP63 and impaired normal TGFβ-trigged epithelial-to-mesenchymal transition. Taken together, these data indicate that PHF14 and HMG20A cooperate in regulating several pathways involved in epithelial–mesenchymal plasticity. Oxford University Press 2022-09-16 /pmc/articles/PMC9508832/ /pubmed/36124662 http://dx.doi.org/10.1093/nar/gkac766 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Gene regulation, Chromatin and Epigenetics Gómez-Marín, Elena Posavec-Marjanović, Melanija Zarzuela, Laura Basurto-Cayuela, Laura Guerrero-Martínez, José A Arribas, Gonzalo Yerbes, Rosario Ceballos-Chávez, María Rodríguez-Paredes, Manuel Tomé, Mercedes Durán, Raúl V Buschbeck, Marcus Reyes, José C The high mobility group protein HMG20A cooperates with the histone reader PHF14 to modulate TGFβ and Hippo pathways |
title | The high mobility group protein HMG20A cooperates with the histone reader PHF14 to modulate TGFβ and Hippo pathways |
title_full | The high mobility group protein HMG20A cooperates with the histone reader PHF14 to modulate TGFβ and Hippo pathways |
title_fullStr | The high mobility group protein HMG20A cooperates with the histone reader PHF14 to modulate TGFβ and Hippo pathways |
title_full_unstemmed | The high mobility group protein HMG20A cooperates with the histone reader PHF14 to modulate TGFβ and Hippo pathways |
title_short | The high mobility group protein HMG20A cooperates with the histone reader PHF14 to modulate TGFβ and Hippo pathways |
title_sort | high mobility group protein hmg20a cooperates with the histone reader phf14 to modulate tgfβ and hippo pathways |
topic | Gene regulation, Chromatin and Epigenetics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9508832/ https://www.ncbi.nlm.nih.gov/pubmed/36124662 http://dx.doi.org/10.1093/nar/gkac766 |
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