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Nucleic Acids Res. 2018 Apr 20;46(7):3351-3365. doi: 10.1093/nar/gky093.

Lineage specific transcription factors and epigenetic regulators mediate TGFβ-dependent enhancer activation.

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Department of Molecular Genomics. Instituto de Biología Molecular de Barcelona (IBMB), Consejo Superior de Investigaciones Científicas (CSIC), Barcelona 08028, Spain.
Vall d'Hebron Institute of Research (VHIR), Passeig de la Vall d'Hebron, 119; E-08035 Barcelona, Spain. Institut Català per la Recerca i Estudis Avançats (ICREA), Barcelona 08018, Spain.
Center for Molecular Medicine Cologne (CMMC), University of Cologne, Robert-Koch-Strasse 21, 50931 Cologne, Germany.
Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, Consejo Superior de Investigaciones Científicas (CSIC)-Universidad de Sevilla-Universidad Pablo de Olavide, Av. Americo Vespucio 41092 Seville, Spain.


During neurogenesis, dynamic developmental cues, transcription factors and histone modifying enzymes regulate the gene expression programs by modulating the activity of neural-specific enhancers. How transient developmental signals coordinate transcription factor recruitment to enhancers and to which extent chromatin modifiers contribute to enhancer activity is starting to be uncovered. Here, we take advantage of neural stem cells as a model to unravel the mechanisms underlying neural enhancer activation in response to the TGFβ signaling. Genome-wide experiments demonstrate that the proneural factor ASCL1 assists SMAD3 in the binding to a subset of enhancers. Once located at the enhancers, SMAD3 recruits the histone demethylase JMJD3 and the remodeling factor CHD8, creating the appropriate chromatin landscape to allow enhancer transcription and posterior gene activation. Finally, to analyze the phenotypical traits owed to cis-regulatory regions, we use CRISPR-Cas9 technology to demonstrate that the TGFβ-responsive Neurog2 enhancer is essential for proper neuronal polarization.

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