JNK-dependent gene regulatory circuitry governs mesenchymal fate

• Sanjeeb Kumar Sahu ^[2] ; Angela Garding ^[2] ; Neha Tiwari ^[4] ; Sudhir Thakurela ^[2] ; Joern Toedling ^[2] ; Susanne Gebhard ^[1] ; Felipe Ortega ^[4] ; Nikolai Schmarowski ^[3] ; Benedikt Berninger ^[4] ; Robert Nitsch ^[3] ; Marcus Schmidt ^[1] ; Vijay K Tiwari ^[2]
  1. [1] Johannes Gutenberg University of Mainz

     Johannes Gutenberg University of Mainz

     Kreisfreie Stadt Mainz, Alemania

     
  2. [2] Institute of Molecular Biology

     Institute of Molecular Biology

     Kreisfreie Stadt Mainz, Alemania

     
  3. [3] 4 Institute for Microscopic Anatomy and Neurobiology, University Medical Center, Johannes Gutenberg University Mainz, Germany
  4. [4] 2 Institute of Physiological Chemistry, University Medical Center, Johannes Gutenberg University Mainz, Germany

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 34, Nº. 16, 2015, págs. 2162-2181
• Idioma: inglés
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  • The epithelial to mesenchymal transition (EMT) is a biological process in which cells lose cell–cell contacts and become motile. EMT is used during development, for example, in triggering neural crest migration, and in cancer metastasis. Despite progress, the dynamics of JNK signaling, its role in genomewide transcriptional reprogramming, and involved downstream effectors during EMT remain largely unknown. Here, we show that JNK is not required for initiation, but progression of phenotypic changes associated with EMT. Such dependency resulted from JNK-driven transcriptional reprogramming of critical EMT genes and involved changes in their chromatin state. Furthermore, we identified eight novel JNK-induced transcription factors that were required for proper EMT. Three of these factors were also highly expressed in invasive cancer cells where they function in gene regulation to maintain mesenchymal identity. These factors were also induced during neuronal development and function in neuronal migration in vivo. These comprehensive findings uncovered a kinetically distinct role for the JNK pathway in defining the transcriptome that underlies mesenchymal identity and revealed novel transcription factors that mediate these responses during development and disease.