Uveal melanoma (UM), though a rare cancer affecting only about 5 per million adults, is the most common primary eye tumor. BAP1 (BRCA1-associated protein 1) inactivation is a critical mutation associated with metastasis and poor prognosis. BAP1 deubiquitinates histone H2A lysine 119 (H2AK119ub, known for gene silencing) and thereby activates chromatin and gene expression. Here, we analyse data from 11 BAP1-positive and 12 BAP1-negative UM patient tumor samples, integrating genetic, epigenetic, and transcriptomic information, to better understand the role of K119ub in gene expression regulation in these tumor subgroups. We first confirmed that transcriptomes of BAP1-positive and BAP1-negative subgroups were clearly separated. This was mostly due to differential gene regulation, and not to gene copy number variations. Overall, more genes had higher expression levels in BAP1-positive tumors, in agreement with an activating function of BAP1. However, notably many genes were also more expressed in BAP1-negative samples. We next sought to relate gene expression with chromatin state differences considering 5 histone modifications (H2AK119 ubiquitination, H3K27 tri-methylation, H3K27 acetylation, H3K4 mono-methylation and H3K4 tri-methylation). Inferred chromatin states largely agreed with measured chromatin accessibility by ATAC-Seq. Surprisingly, around transcription start sites, repressive chromatin, characterized by K27me3 and K119ub, was more abundant in BAP1-positive than BAP1-negative samples. In contrast, in BAP1-negative tumors, K119ub more often co-localized with K4me1 in this region, including in active chromatin states together with K27ac and K4me3. Active chromatin states without K119ub were more abundant in BAP1-positive samples, as expected. Overall, chromatin states agreed with gene expression in BAP1 subgroups.

Co-authors: Adeline Berger, Nicolas Guex, Alexandre Moulin