Super-enhancers orchestrate transcriptional dysregulation and metabolic reprogramming in uveal melanoma.

IF 5.2 1区 生物学 Q1 BIOLOGY
Hui Pan, Weihuan Shao, Huixue Wang, Shengfang Ge, Lingyu Zhang, Xiaofang Xu, Yefei Wang, Ai Zhuang
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引用次数: 0

Abstract

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.

超级增强子协调葡萄膜黑色素瘤的转录失调和代谢重编程。
葡萄膜黑色素瘤(Uveal melanoma, UM)是成人最常见的眼内恶性肿瘤,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的遗传景观方面进展迅速,但UM发病机制的表观遗传结构仍然不完全清楚。在这里,我们通过基因组级组蛋白乙酰化和转录谱描述了一个超增强子介导的表观遗传管道。我们首先通过染色质免疫沉淀测序(ChIP-seq)表征了UM中超增强子谱的活性景观。我们确定了由UM特异性超级增强子驱动的主转录因子,并且我们的管道确定了转录因子AP-2 α (TFAP2A),它与代谢和肿瘤发生高度相关,是UM的顶级必需调节因子。TFAP2A在UM中占据了与癌基因溶质载体家族7成员8 (SLC7A8)相关的预测超增强子,从而阐明了调节癌基因表达的机制。总的来说,我们的数据说明了UM中超增强子介导的癌基因依赖的表观遗传靶向的潜力,强调了可以用于精确治疗的表观遗传脆弱性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Communications Biology
Communications Biology Medicine-Medicine (miscellaneous)
CiteScore
8.60
自引率
1.70%
发文量
1233
审稿时长
13 weeks
期刊介绍: Communications Biology is an open access journal from Nature Research publishing high-quality research, reviews and commentary in all areas of the biological sciences. Research papers published by the journal represent significant advances bringing new biological insight to a specialized area of research.
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