Transcriptional Reprogramming by AP-1-Bound Cis-Regulatory Elements Is Associated with Melanoma Development

Area of Science:

• Oncology
• Molecular Biology
• Epigenetics

Background:

• Malignant melanoma exhibits high metastatic potential and cellular plasticity.
• Melanoma progression involves genetic alterations, epigenetic reprogramming, and transcriptional changes mediated by transcription factors.
• The AP-1 family, including c-Jun and Fra-1, promotes an invasive cell state through angiogenesis and migration.

Purpose of the Study:

• To investigate the role of AP-1 members c-Jun and Fra-1 in enhancer-mediated gene regulation during melanoma development.
• To elucidate the AP-1-driven regulatory landscape and its impact on melanoma plasticity.

Main Methods:

• Integrative analysis of ChIP-seq and RNA-seq data.
• Identification of enhancer reprogramming during tumor formation.
• Assessment of c-Jun/Fra-1 binding at enhancer regions and chromatin accessibility.

Main Results:

• Extensive enhancer reprogramming occurs during melanoma tumor formation.
• Genes annotated to gained enhancers in melanoma cells are significantly upregulated.
• Approximately 50% of gained enhancers are directly bound by c-Jun/Fra-1, showing high AP-1 motif rates and accessibility.
• Genes linked to c-Jun/Fra-1-bound enhancers are associated with invasive phenotypes, migration, and epithelial-to-mesenchymal transition (EMT).

Conclusions:

• c-Jun and Fra-1 are critical regulators of melanoma development via enhancer-mediated transcriptional programs.
• High expression of c-Jun/Fra-1 and their target genes correlates with poor survival in specific melanoma patient groups (BRAF wild-type, NRAS mutant).
• c-Jun/Fra-1 represent potential biomarkers and therapeutic targets for melanoma.