title: JNK-dependent gene regulatory circuitry governs mesenchymal fate.
abstract: 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.
authors.affiliation: Institute of Molecular Biology (IMB), Mainz, Germany.
authors.forename: Sanjeeb Kumar
authors.initials: SK
authors.lastname: Sahu
authors.affiliation: Institute of Molecular Biology (IMB), Mainz, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Garding
authors.affiliation: Institute of Physiological Chemistry University Medical Center Johannes Gutenberg University, Mainz, Germany.
authors.forename: Neha
authors.initials: N
authors.lastname: Tiwari
authors.affiliation: Institute of Molecular Biology (IMB), Mainz, Germany.
authors.forename: Sudhir
authors.initials: S
authors.lastname: Thakurela
authors.affiliation: Institute of Molecular Biology (IMB), Mainz, Germany.
authors.forename: Joern
authors.initials: J
authors.lastname: Toedling
authors.affiliation: Department of Obstetrics and Gynecology, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Gebhard
authors.affiliation: Institute of Physiological Chemistry University Medical Center Johannes Gutenberg University, Mainz, Germany.
authors.forename: Felipe
authors.initials: F
authors.lastname: Ortega
authors.affiliation: Institute for Microscopic Anatomy and Neurobiology University Medical Center Johannes Gutenberg University, Mainz, Germany.
authors.forename: Nikolai
authors.initials: N
authors.lastname: Schmarowski
authors.affiliation: Institute of Physiological Chemistry University Medical Center Johannes Gutenberg University, Mainz, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Berninger
authors.affiliation: Institute for Microscopic Anatomy and Neurobiology University Medical Center Johannes Gutenberg University, Mainz, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Nitsch
authors.affiliation: Department of Obstetrics and Gynecology, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Schmidt
authors.affiliation: Institute of Molecular Biology (IMB), Mainz, Germany v.tiwari@imb-mainz.de.
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Tiwari
mesh_terms: D002453:Cell Cycle; D002454:Cell Differentiation; D002460:Cell Line; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008648:Mesoderm / Q000502:physiology*; D059008:Time-Lapse Imaging; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D014157:Transcription Factors; D048670:MAP Kinase Kinase 4
keywords: EMT; JNK signaling; gene regulation; metastasis; transcription factors