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The TFEB-TGIF1 axis regulates EMT in mouse epicardial cells

Author

Listed:
  • Elena Astanina

    (University of Torino
    Candiolo Cancer Institute-IRCCS-FPO)

  • Gabriella Doronzo

    (University of Torino
    Candiolo Cancer Institute-IRCCS-FPO)

  • 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
    Candiolo Cancer Institute-IRCCS-FPO)

  • Edoardo Vallariello

    (University of Torino
    Candiolo Cancer Institute-IRCCS-FPO)

  • Chiara Cencioni

    (National Research Council (IASI-CNR))

  • Donatella Valdembri

    (University of Torino
    Candiolo Cancer Institute-IRCCS-FPO)

  • Guido Serini

    (University of Torino
    Candiolo Cancer Institute-IRCCS-FPO)

  • Federica Limana

    (San Raffaele Open University
    IRCCS San Raffaele Pisana)

  • Eleonora Foglio

    (Technoscience, Parco Scientifico e Tecnologico Pontino)

  • Andrea Ballabio

    (Telethon Institute of Genetics and Medicine (TIGEM)
    Federico II University
    Baylor College of Medicine
    Texas Children’s Hospital)

  • Federico Bussolino

    (University of Torino
    Candiolo Cancer Institute-IRCCS-FPO)

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.

Suggested Citation

  • Elena Astanina & Gabriella Doronzo & Davide Corà & Francesco Neri & Salvatore Oliviero & Tullio Genova & Federico Mussano & Emanuele Middonti & Edoardo Vallariello & Chiara Cencioni & Donatella Valdem, 2022. "The TFEB-TGIF1 axis regulates EMT in mouse epicardial cells," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32855-3
    DOI: 10.1038/s41467-022-32855-3
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    References listed on IDEAS

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    1. Kristy Red-Horse & Hiroo Ueno & Irving L. Weissman & Mark A. Krasnow, 2010. "Coronary arteries form by developmental reprogramming of venous cells," Nature, Nature, vol. 464(7288), pages 549-553, March.
    2. Vincent M. Christoffels & Thomas Grieskamp & Julia Norden & Mathilda T. M. Mommersteeg & Carsten Rudat & Andreas Kispert, 2009. "Tbx18 and the fate of epicardial progenitors," Nature, Nature, vol. 458(7240), pages 8-9, April.
    3. Nunzia Pastore & Tuong Huynh & Niculin J. Herz & Alessia Calcagni’ & Tiemo J. Klisch & Lorenzo Brunetti & Kangho Ho Kim & Marco De Giorgi & Ayrea Hurley & Annamaria Carissimo & Margherita Mutarelli & , 2020. "TFEB regulates murine liver cell fate during development and regeneration," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    4. Chen-Leng Cai & Jody C. Martin & Yunfu Sun & Li Cui & Lianchun Wang & Kunfu Ouyang & Lei Yang & Lei Bu & Xingqun Liang & Xiaoxue Zhang & William B. Stallcup & Christopher P. Denton & Andrew McCulloch , 2008. "A myocardial lineage derives from Tbx18 epicardial cells," Nature, Nature, vol. 454(7200), pages 104-108, July.
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