title: Decoding the regulatory landscape of melanoma reveals TEADS as regulators of the invasive cell state.
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.
authors: Laboratory of Computational Biology, Center for Human Genetics, University of Leuven, 3000 Leuven, Belgium.
authors: Annelien
authors: A
authors: Verfaillie
authors: Laboratory of Computational Biology, Center for Human Genetics, University of Leuven, 3000 Leuven, Belgium.
authors: Hana
authors: H
authors: Imrichova
authors: Laboratory of Computational Biology, Center for Human Genetics, University of Leuven, 3000 Leuven, Belgium.
authors: Zeynep Kalender
authors: ZK
authors: Atak
authors: 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.
authors: Michael
authors: M
authors: Dewaele
authors: 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.
authors: Florian
authors: F
authors: Rambow
authors: Laboratory of Computational Biology, Center for Human Genetics, University of Leuven, 3000 Leuven, Belgium.
authors: Gert
authors: G
authors: Hulselmans
authors: Laboratory of Computational Biology, Center for Human Genetics, University of Leuven, 3000 Leuven, Belgium.
authors: Valerie
authors: V
authors: Christiaens
authors: Laboratory of Computational Biology, Center for Human Genetics, University of Leuven, 3000 Leuven, Belgium.
authors: Dmitry
authors: D
authors: Svetlichnyy
authors: 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.
authors: Flavie
authors: F
authors: Luciani
authors: 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.
authors: Laura
authors: L
authors: Van den Mooter
authors: 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.
authors: Sofie
authors: S
authors: Claerhout
authors: VIB Center for the Biology of Disease, 3000 Leuven, Belgium.
authors: Mark
authors: M
authors: Fiers
authors: Medical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles, 1000 Brussels, Belgium.
authors: Fabrice
authors: F
authors: Journe
authors: Medical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles, 1000 Brussels, Belgium.
authors: Ghanem-Elias
authors: GE
authors: Ghanem
authors: Department of Theoretical Bioinformatics, DKFZ Heidelberg, 69117 Heidelberg, Germany.
authors: Carl
authors: C
authors: Herrmann
authors: 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.
authors: Georg
authors: G
authors: Halder
authors: 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.
authors: Jean-Christophe
authors: JC
authors: Marine
authors: Laboratory of Computational Biology, Center for Human Genetics, University of Leuven, 3000 Leuven, Belgium.
authors: Stein
authors: S
authors: Aerts
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D065150:Cellular Reprogramming / Q000235:genetics; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D055757:SOXE Transcription Factors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000091262:TEA Domain Transcription Factors; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D059467:Transcriptome
chemical_list: D000970:Antineoplastic Agents; D002843:Chromatin; D004268:DNA-Binding Proteins; D006657:Histones; C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; D009687:Nuclear Proteins; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; C527923:SOX10 protein, human; D055757:SOXE Transcription Factors; D000091262:TEA Domain Transcription Factors; C057182:TEAD1 protein, human; D018808:Transcription Factor AP-1; D014157:Transcription Factors