JMJD3 intrinsically disordered region links the 3D-genome structure to TGFβ-dependent transcription activation

Marta Vicioso-Mantis, Raquel Fueyo, Claudia Navarro, Sara Cruz-Molina, Wilfred F. J. Ijcken, Elena Rebollo, Álvaro Rada-Iglesias and Marian A. Martínez-Balbás ()
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Marta Vicioso-Mantis: Consejo Superior de Investigaciones Científicas (CSIC)
Raquel Fueyo: Consejo Superior de Investigaciones Científicas (CSIC)
Claudia Navarro: Consejo Superior de Investigaciones Científicas (CSIC)
Sara Cruz-Molina: University of Cologne
Wilfred F. J. Ijcken: Erasmus University Medical Center Rotterdam
Elena Rebollo: Consejo Superior de Investigaciones Científicas (CSIC)
Álvaro Rada-Iglesias: University of Cologne
Marian A. Martínez-Balbás: Consejo Superior de Investigaciones Científicas (CSIC)

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract Enhancers are key regulatory elements that govern gene expression programs in response to developmental signals. However, how multiple enhancers arrange in the 3D-space to control the activation of a specific promoter remains unclear. To address this question, we exploited our previously characterized TGFβ-response model, the neural stem cells, focusing on a ~374 kb locus where enhancers abound. Our 4C-seq experiments reveal that the TGFβ pathway drives the assembly of an enhancer-cluster and precise gene activation. We discover that the TGFβ pathway coactivator JMJD3 is essential to maintain these structures. Using live-cell imaging techniques, we demonstrate that an intrinsically disordered region contained in JMJD3 is involved in the formation of phase-separated biomolecular condensates, which are found in the enhancer-cluster. Overall, in this work we uncover novel functions for the coactivator JMJD3, and we shed light on the relationships between the 3D-conformation of the chromatin and the TGFβ-driven response during mammalian neurogenesis.

Date: 2022
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DOI: 10.1038/s41467-022-30614-y

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