Decoding the regulatory landscape of melanoma reveals TEADS as regulators of the invasive cell state

Annelien Verfaillie, Hana Imrichova, Zeynep Kalender Atak, Michael Dewaele, Florian Rambow, Gert Hulselmans, Valerie Christiaens, Dmitry Svetlichnyy, Flavie Luciani, Laura Van den Mooter, Sofie Claerhout, Mark Fiers, Fabrice Journe, Ghanem-Elias Ghanem, Carl Herrmann, Georg Halder, Jean-Christophe Marine and Stein Aerts ()
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Annelien Verfaillie: Laboratory of Computational Biology, Center for Human Genetics, University of Leuven
Hana Imrichova: Laboratory of Computational Biology, Center for Human Genetics, University of Leuven
Zeynep Kalender Atak: Laboratory of Computational Biology, Center for Human Genetics, University of Leuven
Michael Dewaele: Laboratory for Molecular Cancer Biology, Center for Human Genetics, University of Leuven
Florian Rambow: Laboratory for Molecular Cancer Biology, Center for Human Genetics, University of Leuven
Gert Hulselmans: Laboratory of Computational Biology, Center for Human Genetics, University of Leuven
Valerie Christiaens: Laboratory of Computational Biology, Center for Human Genetics, University of Leuven
Dmitry Svetlichnyy: Laboratory of Computational Biology, Center for Human Genetics, University of Leuven
Flavie Luciani: Laboratory for Molecular Cancer Biology, Center for Human Genetics, University of Leuven
Laura Van den Mooter: VIB Center for the Biology of Disease
Sofie Claerhout: VIB Center for the Biology of Disease
Mark Fiers: VIB Center for the Biology of Disease
Fabrice Journe: Medical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles
Ghanem-Elias Ghanem: Medical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles
Carl Herrmann: DKFZ Heidelberg
Georg Halder: VIB Center for the Biology of Disease
Jean-Christophe Marine: Laboratory for Molecular Cancer Biology, Center for Human Genetics, University of Leuven
Stein Aerts: Laboratory of Computational Biology, Center for Human Genetics, University of Leuven

Nature Communications, 2015, vol. 6, issue 1, 1-16

Abstract: Abstract Transcriptional reprogramming of proliferative melanoma cells into a phenotypically distinct invasive cell subpopulation is a critical event at the origin of metastatic spreading. Here we generate transcriptome, open chromatin and histone modification maps of melanoma cultures; and integrate this data with existing transcriptome and DNA methylation profiles from tumour biopsies to gain insight into the mechanisms underlying this key reprogramming event. This shows thousands of genomic regulatory regions underlying the proliferative and invasive states, identifying SOX10/MITF and AP-1/TEAD as regulators, respectively. Knockdown of TEADs shows a previously unrecognized role in the invasive gene network and establishes a causative link between these transcription factors, cell invasion and sensitivity to MAPK inhibitors. Using regulatory landscapes and in silico analysis, we show that transcriptional reprogramming underlies the distinct cellular states present in melanoma. Furthermore, it reveals an essential role for the TEADs, linking it to clinically relevant mechanisms such as invasion and resistance.

Date: 2015
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DOI: 10.1038/ncomms7683

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