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

作者：Verfaillie Annelien; Imrichova Hana; Atak Zeynep Kalender; Dewaele Michael; Rambow Florian; Hulselmans Gert; Christiaens Valerie; Svetlichnyy Dmitry; Luciani Flavie; Van den Mooter Laura; Claerhout Sofie; Fiers Mark; Journe Fabrice; Ghanem Ghanem Elias; Herrmann Carl; Halder Georg; Marine Jean Christophe; Aerts Stein

来源：Nature Communications, 2015, 6(1): 6683.

DOI：10.1038/ncomms7683

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.

• 出版日期2015-4