DataSheet_1_Global CpG DNA Methylation Footprint in Kaposi’s Sarcoma.pdf

Kaposi’s sarcoma-associated herpesvirus (KSHV), also familiar as human herpesvirus 8 (HHV-8), is one of the well-known human cancer-causing viruses. KSHV was originally discovered by its association with Kaposi’s sarcoma (KS), a common AIDS-related neoplasia. Additionally, KSHV is associated with two B-lymphocyte disorders; primary effusion lymphoma (PEL) and Multicentric Castlemans Disease (MCD). DNA methylation is an epigenetic modification that is essential for a properly functioning human genome through its roles in chromatin structure maintenance, chromosome stability and transcription regulation. Genomic studies show that expressed promoters tend to be un-methylated whereas methylated promoters tend to be inactive. We have previously revealed the global methylation footprint in PEL cells and found that many cellular gene promoters become differentially methylated and hence differentially expressed in KSHV chronically infected PEL cell lines. Here we present the cellular CpG DNA methylation footprint in KS, the most common malignancy associated with KSHV. We performed MethylationEPIC BeadChip to compare the global methylation status in normal skin compared to KS biopsies, and revealed dramatic global methylation alterations occurring in KS. Many of these changes were attributed to hyper-methylation of promoters and enhancers that regulate genes associated with abnormal skin morphology, a well-known hallmark of KS development. We observed six-fold increase in hypo-methylated CpGs between early stage of KS (plaque) and the more progressed stage (nodule). These observations suggest that hyper-methylation takes place early in KS while hypo-methylation is a later process that is more significant in nodule. Our findings add another layer to the understanding of the relationship between epigenetic changes caused by KSHV infection and tumorigenesis.

卡波西肉瘤相关疱疹病毒（KSHV），亦称人疱疹病毒8型（HHV-8），是已知的人体致癌病毒之一。KSHV最初因与卡波西肉瘤（KS）的关联而被发现，卡波西肉瘤是一种常见的与艾滋病相关的肿瘤。此外，KSHV还与两种B淋巴细胞疾病相关；原发渗出性淋巴瘤（PEL）和多中心Castleman病（MCD）。DNA甲基化是一种表观遗传修饰，通过其在染色质结构维持、染色体稳定性和转录调控中的作用，对于人类基因组正常功能至关重要。基因组研究表明，表达的启动子往往未发生甲基化，而甲基化的启动子往往处于非活性状态。我们先前揭示了PEL细胞中的全局甲基化足迹，并发现许多细胞基因启动子在KSHV慢性感染的PEL细胞系中发生差异甲基化，从而表现出差异表达。在本研究中，我们展示了KS（KSHV最常见的相关恶性肿瘤）中的细胞CpG DNA甲基化足迹。我们进行了MethylationEPIC BeadChip的比较，以比较正常皮肤与KS活检之间的全局甲基化状态，并揭示了在KS中发生的显著的全局甲基化改变。其中许多变化归因于调节与异常皮肤形态相关基因的启动子和增强子的过度甲基化，这是KS发展的一个已知标志。我们在KS的早期阶段（斑块）与更进展的阶段（结节）之间观察到CpG的低甲基化增加了六倍。这些观察结果表明，过度甲基化在KS的早期阶段发生，而低甲基化是一个更晚期的过程，在结节阶段更为显著。我们的发现为理解KSHV感染引起的表观遗传变化与肿瘤发生之间的关系增添了新的层次。