Abstract Loss-of-function mutations of the epigenetic regulator BAP1, the catalytic subunit of the PR-DUB complex, are among the strongest predictors of metastasis in uveal melanoma (UM). Although BAP1 loss is known to disrupt chromatin organization, the specific epigenetic mechanisms that reshape cell identity and promote tumor progression remain poorly defined. Here, we investigated the epigenomic rewiring driven by BAP1 loss using ATAC-seq, reduced-representation bisulfite sequencing, histone modification profiling, and RNA-seq across three BAP1-wildtype and three BAP1-mutant UM cell lines, as well as a normal human uveal melanocyte (UMC) cell line and its isogenic BAP1-knockout counterpart. This design enabled us to isolate the BAP1-dependent chromatin and transcriptional changes in both normal and transformed uveal cells. BAP1-mutant UM displayed coordinated activation of angiogenic and neuronal-mimicry gene programs, accompanied by suppression of immune and inflammatory signaling. Chromatin accessibility analyses revealed a broad reduction of SOX family activity in both UM and melanocyte models lacking BAP1, suggesting that BAP1 maintains lineage-defining SOX programs. In parallel, we identified a distinct set of transcription factors consistently enriched across all UM lines, independent of BAP1 status, highlighting conserved regulatory networks underlying UM biology. DNA methylation profiling uncovered an unexpected global hypomethylation phenotype in BAP1-mutant UM, further highlighting a broader role for BAP1 in maintaining epigenomic organization. Together, these data reveal the multilayered epigenomic consequences of BAP1 mutations and identify regulatory circuits driven by BAP1 loss that drive tumor progression and metastasis in uveal melanoma. Citation Format: Gulum Yenisehirli, Aristeidis G. Telonis, Renata L. Volonterio, Monica Lopez, Jeffim N. Kuznetsoff, Ashley N. Zuniga, J. William Harbour, Zelia M. Correa, Stefan Kurtenbach. Epigenomic rewiring driven by BAP1 loss in uveal melanoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3230.
Yenisehirli et al. (2026) studied this question.