The TFEB-TGIF1 axis regulates EMT in mouse epicardial cells

Elena Astanina (), Gabriella Doronzo, Davide Corà, Francesco Neri, Salvatore Oliviero, Tullio Genova, Federico Mussano, Emanuele Middonti, Edoardo Vallariello, Chiara Cencioni, Donatella Valdembri, Guido Serini, Federica Limana, Eleonora Foglio, Andrea Ballabio and Federico Bussolino
Additional contact information
Elena Astanina: University of Torino
Gabriella Doronzo: University of Torino
Davide Corà: Università degli Studi del Piemonte Orientale
Francesco Neri: University of Torino
Salvatore Oliviero: University of Torino
Tullio Genova: University of Torino
Federico Mussano: University of Torino
Emanuele Middonti: University of Torino
Edoardo Vallariello: University of Torino
Chiara Cencioni: National Research Council (IASI-CNR)
Donatella Valdembri: University of Torino
Guido Serini: University of Torino
Federica Limana: San Raffaele Open University
Eleonora Foglio: Technoscience, Parco Scientifico e Tecnologico Pontino
Andrea Ballabio: Telethon Institute of Genetics and Medicine (TIGEM)
Federico Bussolino: University of Torino

Nature Communications, 2022, vol. 13, issue 1, 1-20

Abstract: Abstract Epithelial-mesenchymal transition (EMT) is a complex and pivotal process involved in organogenesis and is related to several pathological processes, including cancer and fibrosis. During heart development, EMT mediates the conversion of epicardial cells into vascular smooth muscle cells and cardiac interstitial fibroblasts. Here, we show that the oncogenic transcription factor EB (TFEB) is a key regulator of EMT in epicardial cells and that its genetic overexpression in mouse epicardium is lethal due to heart defects linked to impaired EMT. TFEB specifically orchestrates the EMT-promoting function of transforming growth factor (TGF) β, and this effect results from activated transcription of thymine-guanine-interacting factor (TGIF)1, a TGFβ/Smad pathway repressor. The Tgif1 promoter is activated by TFEB, and in vitro and in vivo findings demonstrate its increased expression when Tfeb is overexpressed. Furthermore, Tfeb overexpression in vitro prevents TGFβ-induced EMT, and this effect is abolished by Tgif1 silencing. Tfeb loss of function, similar to that of Tgif1, sensitizes cells to TGFβ, inducing an EMT response to low doses of TGFβ. Together, our findings reveal an unexpected function of TFEB in regulating EMT, which might provide insights into injured heart repair and control of cancer progression.

Date: 2022
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DOI: 10.1038/s41467-022-32855-3

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