Cutaneous melanoma is rapidly on the rise globally, surpassing the growth rate of other cancers, with metastasis being the primary cause of death in melanoma patients. Consequently, understanding the mechanisms behind this metastatic process and exploring innovative treatments is of paramount importance. Recent research has shown promise in unravelling the role of epigenetic factors in melanoma progression to metastasis. While DNA hypermethylation at gene promoters typically suppresses gene expression, we have contributed to establishing the newly understood mechanism of paradoxical activation of genes via DNA methylation, where high methylation coincides with increased gene activity. This mechanism challenges the conventional paradigm that promoter methylation solely silences genes, suggesting that, for specific genes, it might actually activate them. Traditionally, altering DNA methylation in vitro has involved using global demethylating agents, which is insufficient for studying the mechanism and testing the direct consequence of gene methylation changes. To investigate promoter hypermethylation and its association with gene activation, we employed a novel approach utilising a CRISPR-SunTag All-in-one system. Here, we focused on editing the DNA methylation of a specific gene promoter segment (EBF3) in melanoma cells using the All-in-one system. Using bisulfite sequencing and qPCR with RNA-Seq, we successfully demonstrated highly effective methylation and demethylation of the EBF3 promoter, with subsequent gene expression changes, to establish and validate the paradoxical role of DNA methylation. Further, our study provides novel insights into the function of the EBF3 gene, which remains largely unknown. Overall, this study challenges the conventional view of methylation as solely a gene-silencing mechanism and demonstrates a potential function of EBF3 in IFN pathway signalling, potentially uncovering new insights into epigenetic drivers of malignancy and metastasis.

Clinical epigenetics as a field has experienced rapid advancement over recent decades. Complexities of fundamental epigenetic regulation in health and disease continue to be uncovered, alongside developments in novel epigenetic technologies and clinical applications. The 4th Clinical Epigenetics International Conference (CLEPIC) held 11th -13th June 2025 at The University of Campania Luigi Vanvitelli in Naples, Italy, highlighted exciting progress across a range of areas. Here, we provide an overview of the broad themes and emerging concepts explored during this meeting and discuss prospects for further research and clinical translation.

Prostate cancer (PCa) is a major health burden worldwide, and despite early treatment, many patients present with biochemical recurrence (BCR) post-treatment, reflected by a rise in prostate-specific antigen (PSA) over a clinical threshold. Novel transcriptomic and epigenomic biomarkers can provide a powerful tools for the clinical management of PCa. Here, we provide matched RNA sequencing and array-based genome-wide DNA methylome data of PCa patients (n = 17) with or without evidence of BCR following radical prostatectomy. Formalin-fixed paraffin-embedded (FFPE) tissues were used to generate these data, which included technical replicates to provide further validity of the data. We describe the sample features, experimental design, methods and bioinformatic pipelines for processing these multi-omic data. Importantly, comprehensive clinical, histopathological, and follow-up data for each patient were provided to enable the correlation of transcriptome and methylome features with clinical features. Our data will contribute towards the efforts of developing epigenomic and transcriptomic markers for BCR and also facilitate a deeper understanding of the molecular basis of PCa recurrence.