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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
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.
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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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