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Nat Commun. 2015 Apr 9;6:6683. doi: 10.1038/ncomms7683.

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

Author information

1
Laboratory of Computational Biology, Center for Human Genetics, University of Leuven, 3000 Leuven, Belgium.
2
1] Laboratory for Molecular Cancer Biology, Center for Human Genetics, University of Leuven, 3000 Leuven, Belgium [2] VIB Center for the Biology of Disease, 3000 Leuven, Belgium.
3
1] VIB Center for the Biology of Disease, 3000 Leuven, Belgium [2] Laboratory of Growth Control and Cancer Research, Center for Human Genetics, University of Leuven, 3000 Leuven, Belgium.
4
VIB Center for the Biology of Disease, 3000 Leuven, Belgium.
5
Medical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles, 1000 Brussels, Belgium.
6
Department of Theoretical Bioinformatics, DKFZ Heidelberg, 69117 Heidelberg, Germany.

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.

PMID:
25865119
PMCID:
PMC4403341
DOI:
10.1038/ncomms7683
[Indexed for MEDLINE]
Free PMC Article

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