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

Veronica Davalos, Claudia D. Lovell, Richard Von Itter, Igor Dolgalev, Praveen Agrawal, Gillian Baptiste, David J. Kahler, Elena Sokolova, Sebastian Moran, Laia Piqué, Eleazar Vega-Saenz de Miera, Barbara Fontanals-Cirera, Alcida Karz, Aristotelis Tsirigos, Chi Yun, Farbod Darvishian, Heather C. Etchevers, Iman Osman, Manel Esteller, Markus SchoberEva Hernando

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

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 melanoma progression 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.

Original languageEnglish (US)
Article number1867
JournalNature communications
Volume14
Issue number1
DOIs
StatePublished - Dec 2023

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy

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