Pan Hui, Shao Weihuan, Wang Huixue, Ge Shengfang, Zhang Lingyu, Xu Xiaofang, Wang Yefei, Zhuang Ai
State Key Laboratory of Eye Health, Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China.
Commun Biol. 2025 Jun 23;8(1):951. doi: 10.1038/s42003-025-08338-8.
Uveal melanoma (UM) is the most common intraocular malignancy in adults and frequently metastasizes. Somatic mutations and chromatin aberrations have been implicated in the pathogenesis of this deadly disease. Despite rapid progress in elucidating the genetic landscape of UM, the epigenetic architecture underlying UM pathogenesis remains incompletely understood. Here, we describe a super-enhancer-mediated epigenetic pipeline through genome-scale histone acetylation and transcriptional profiling. We first characterized the active landscape of super-enhancer profiles in UM via chromatin immunoprecipitation sequencing (ChIP-seq). We identified master transcription factors specifically driven by UM-specific super-enhancers, and our pipeline identified transcription factor AP-2 alpha (TFAP2A), which is highly associated with metabolism and oncogenesis, as the top essential regulator in UM. TFAP2A occupied predicted super-enhancers associated with the oncogene Solute Carrier Family 7 member 8 (SLC7A8) in UM, thereby elucidating a mechanism for regulating oncogene expression. Collectively, our data illustrate the potential for epigenetic targeting of super-enhancer-mediated oncogene dependencies in UM, highlighting an epigenetic vulnerability that can be exploited for precision therapy.
葡萄膜黑色素瘤（UM）是成人中最常见的眼内恶性肿瘤，且经常发生转移。体细胞突变和染色质畸变与这种致命疾病的发病机制有关。尽管在阐明UM的遗传格局方面取得了快速进展，但UM发病机制背后的表观遗传结构仍未完全了解。在这里，我们通过全基因组规模的组蛋白乙酰化和转录谱分析描述了一种超级增强子介导的表观遗传途径。我们首先通过染色质免疫沉淀测序（ChIP-seq）对UM中超级增强子图谱的活性格局进行了表征。我们鉴定了由UM特异性超级增强子特异性驱动的主转录因子，并且我们的途径鉴定出与代谢和肿瘤发生高度相关的转录因子AP-2α（TFAP2A）是UM中最重要的调节因子。TFAP2A占据了UM中与癌基因溶质载体家族7成员8（SLC7A8）相关的预测超级增强子，从而阐明了一种调节癌基因表达的机制。总体而言，我们的数据说明了在UM中对超级增强子介导的癌基因依赖性进行表观遗传靶向的潜力，突出了一种可用于精准治疗的表观遗传脆弱性。
