The high mobility group protein HMG20A cooperates with the histone reader PHF14 to modulate TGF and Hippo pathways
|Author/s||Gomez Marin, Elena
Posavec Marjanovic, Melanija
Basurto Cayuela, Laura
Guerrero Martinez, Jose A.
Reyes, Jose C.
|Department||Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica|
|Abstract||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
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 affin- ity 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 af- fects proliferation. Transcriptomic analyses demon- strate that PHF14 and HMG20A share a large sub- set of targets. We show that the PHF14-HMG20A complex modulates the Hippo pathway through a direct interaction with the TEAD1 transcription fac- tor. 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.
|Funding agencies||Ministerio de Economía y Competitividad (MINECO). España
Junta de Andalucía
|Project ID.||PID2020- 118516GB-I00
P18-FR-1962 and BIO-321