BAP1 loss rewires chromatin and lineage identity in uveal melanoma

Background : BAP1 is a chromatin-associated deubiquitinase that antagonizes Polycomb Repressive Complex 1 (PRC1)-mediated ubiquitination, thereby stabilizing chromatin accessibility and genomic integrity. Uveal melanoma is the most common intraocular cancer in adults and loss of BAP1 tracks with a high-risk, metastatic phenotype. However, how BAP1 loss reprograms the epigenetic landscape to drive these lineage and phenotypic changes remains unknown. Our objective is to define the chromatin and transcriptional consequences of BAP1 loss in uveal melanoma. Description of experimental procedures : To identify regulatory mechanisms altered secondary to BAP1 loss, we profiled the epigenome upon BAP1 loss using ATAC-seq, RNA-seq, and CUT&RUN for repressive marks such as H2AK119Ub and H3K27me3. Differential chromatin accessibility was identified using DiffBind, and motif enrichment was performed with HOMER, to infer changes in lineage-defining transcriptional circuits. Multi-omic integration with RNA-seq and public UM datasets (including TCGA) was used to align BAP1-dependent epigenetic states with low and high-risk tumor classes and to connect epigenetic remodeling to lineage states (melanocytic vs neural crest-like). Summary of new results: BAP1 loss induced widespread changes in chromatin accessibility and repressive histone marks, including a global reduction in H2AK119Ub and redistribution of H3K27me3. These alterations were not uniform across the genome: distal elements, particularly on chromosome 8, preferentially lost repressive marks and gained accessibility in BAP1-deficient cells, consistent with enhancer remodeling at loci associated with high-risk uveal melanoma. CUTnRUN and ATAC analyses separated genomic regions into two major subsets: 1) melanocytic-lineage regulatory elements that gained repressive marks and lost accessibility, and 2) regions associated with neural crest-like and invasive programs that became more accessible and enhancer-like. AP-2 motifs were strongly enriched within ATAC-seq peaks that gained accessibility in BAP1-deficient UM, and displayed lower H3K27me3 and H2AK119Ub peaks, reflecting a more permissive chromatin state at these regions relative to indolent UM. Together, these data link BAP1 loss to a coordinated epigenetic shift from a melanocytic toward a neural crest-like epigenetic state. Conclusions: Loss of BAP1 in uveal melanoma is associated with epigenetic remodeling, characterized by redistribution of repressive histone marks, and enhancer reorganization. This epigenetic reprogramming aligns with loss of melanocytic identity and emergence of a neural crest-like invasive state, providing a mechanistic link between BAP1 loss and aggressive tumor behavior.