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