An epigenetic switch controls an alternative NR2F2 isoform 2 that unleashes a metastatic program in melanoma

Verónica Davalos (1) , Claudia Lovell , Richard von Itter , Igor Dolgalev (2) , Praveen Agrawal (1) , Gillian Baptiste (1) , David Kahler , Elena Sokolova (1) , Sebastian Moran (3) , Laia Piqué (4) , Eleazar Vega-Saenz de Miera , Barbara Fontanals-Cirera (1) , Alcida Karz (1) , Aristotelis Tsirigos (5, 1) , Chi Yun (6, 7) , Farbod Darvishian (1) , Heather Etchevers (8, 9) , Iman Osman (10) , Manel Esteller (11, 12, 13, 14) , Markus Schober (15) , Eva Hernando (1)

1 Department of Pathology, New York University Grossman School of Medicine, NY 10016, USA
2 Applied Bioinformatics Laboratories, New York University Grossman School of Medicine, NY 10016, USA
3 Bellvitge Biomedical Research Institute
4 Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Catalonia, Spain
5 NYU Grossman School of Medicine - New York University School of Medicine
6 NTHU - National Tsing Hua University [Hsinchu]
7 CUHK - City University of Hong Kong [Hong Kong]
8 MMG - Marseille medical genetics - Centre de génétique médicale de Marseille
9 MarMaRa - Institut Marseille Maladies Rares
10 NYUSM - Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, New York University School of Medicine, NY 10016, USA
11 ICREA - Institució Catalana de Recerca i Estudis Avançats = Catalan Institution for Research and Advanced Studies
12 IJC - Josep Carreras Leukaemia Research Institute
13 CIBERONC - Centro de Investigación Biomédica en Red de Cáncer
14 UB - Universitat de Barcelona
15 NYU - New York University [New York]

Metastatic melanoma develops once transformed melanocytic cells begin to de-differentiate into migratory and invasive melanoma cells with neural crest cell (NCC)-like and epithelial-to mesenchymal transition (EMT)-like features. However, it is still unclear how transformed melanocytes assume a metastatic melanoma cell state. Here, we define DNA methylation changes that accompany metastatic progression in melanoma patients and discover Nuclear Receptor Subfamily 2 Group F, Member 2 – isoform 2 (NR2F2-Iso2) as an epigenetically regulated metastasis driver. NR2F2-Iso2 is transcribed from an alternative transcriptional start site (TSS) and it is truncated at the N-terminal end which encodes the NR2F2 DNA-binding domain. We find that NR2F2-Iso2 expression is turned off by DNA methylation when NCCs differentiate into melanocytes. Conversely, this process is reversed during metastatic melanoma progression, when NR2F2-Iso2 becomes increasingly hypomethylated and re-expressed. Our functional and molecular studies suggest that NR2F2-Iso2 drives metastatic melanomaprogression by modulating the activity of full-length NR2F2 (Isoform 1) over EMT- and NCC-associated target genes. Our findings indicate that DNA methylation changes play a crucial role during metastatic melanoma progression, and their control of NR2F2 activity allows transformed melanocytes to acquire NCC-like and EMT-like features. This epigenetically regulated transcriptional plasticity facilitates cell state transitions and metastatic spread.

Domaines: Biologie cellulaire; Sciences du Vivant [q-bio]; Cancer; Génétique humaine; Dermatologie

Verónica Davalos, Claudia Lovell, Richard von Itter, Igor Dolgalev, Praveen Agrawal, et al.. An epigenetic switch controls an alternative NR2F2 isoform 2 that unleashes a metastatic program in melanoma. Nature Communications, In press, 14 (1), pp.1867. ⟨10.1038/s41467-023-36967-2⟩. ⟨hal-04007075⟩