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; Stein Aerts

doi:10.1038/ncomms7683

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

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

Authors

Annelien Verfaillie¹, Hana Imrichova¹, Zeynep Kalender Atak¹, Michael Dewaele², Florian Rambow², Gert Hulselmans¹, Valerie Christiaens¹, Dmitry Svetlichnyy¹, Flavie Luciani², Laura Van den Mooter³, Sofie Claerhout³, Mark Fiers⁴, Fabrice Journe⁵, Ghanem-Elias Ghanem⁵, Carl Herrmann⁶, Georg Halder³, Jean-Christophe Marine², Stein Aerts¹

Affiliations

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / pharmacology
Cell Line, Tumor
Cell Transformation, Neoplastic / genetics*
Cell Transformation, Neoplastic / metabolism
Cell Transformation, Neoplastic / pathology
Cellular Reprogramming / genetics
Chromatin / chemistry
Chromatin / metabolism
DNA Methylation
DNA-Binding Proteins / antagonists & inhibitors
DNA-Binding Proteins / genetics*
DNA-Binding Proteins / metabolism
Gene Expression Regulation, Neoplastic*
Gene Regulatory Networks*
Histones / genetics
Histones / metabolism
Humans
Melanoma / drug therapy
Melanoma / genetics*
Melanoma / metabolism
Melanoma / pathology
Microphthalmia-Associated Transcription Factor / genetics
Microphthalmia-Associated Transcription Factor / metabolism
Neoplasm Invasiveness
Nuclear Proteins / antagonists & inhibitors
Nuclear Proteins / genetics*
Nuclear Proteins / metabolism
Protein Isoforms / genetics
Protein Isoforms / metabolism
Protein Kinase Inhibitors / pharmacology
RNA, Small Interfering / genetics
RNA, Small Interfering / metabolism
SOXE Transcription Factors / genetics
SOXE Transcription Factors / metabolism
Signal Transduction
TEA Domain Transcription Factors
Transcription Factor AP-1 / genetics
Transcription Factor AP-1 / metabolism
Transcription Factors / antagonists & inhibitors
Transcription Factors / genetics*
Transcription Factors / metabolism
Transcription, Genetic
Transcriptome*

Substances

Antineoplastic Agents
Chromatin
DNA-Binding Proteins
Histones
MITF protein, human
Microphthalmia-Associated Transcription Factor
Nuclear Proteins
Protein Isoforms
Protein Kinase Inhibitors
RNA, Small Interfering
SOX10 protein, human
SOXE Transcription Factors
TEA Domain Transcription Factors
TEAD1 protein, human
Transcription Factor AP-1
Transcription Factors