Department of Clinical Neuroscience; Karolinska Institutet; Stockholm, Sweden.
Epigenetics. 2012 Jun 1;7(6):585-93. doi: 10.4161/epi.20075.
Human Cytomegalovirus (HCMV) is a ubiquitous herpesvirus that infects and establishes latency in the majority of the human population and may cause fatal infections in immunocompromised patients. Recent data implies a close interaction between HCMV encoded proteins and cellular epigenetic mechanisms such as histone acetylation and deacetylation. In this study, we investigated the interactions between HCMV infection and the DNA methylation machinery in different host cells using several approaches. We found that colon cancer cell line HCT-116 lacking the DNMT1 and DNMT3b methyltransferases was susceptible to HCMV-AD169 infection, while wild-type cells were non-susceptible. Treatment of wild-type HCT-116 cells with 5-azacytidine rendered them susceptible to infection. Further investigation of HCMV infected MRC-5 fibroblasts demonstrated significant global hypomethylation, a phenomenon that was virus strain-specific and associated with the re-localization of DNMT1 and DNMT3b from the nucleus to the cytoplasm. The cytoplasmic accumulation of DNMT1 was also evident in in vitro infected macrophages and in epithelial cells in tissue samples from patients with inflammatory bowel disease and concomitant HCMV infection. Foscavir treatment of virus infected fibroblasts did not affect the majority of the virus induced nuclear exclusion of DNMT1, which suggest that it is dependent on viral IE gene products. In conclusion, HCMV infection results in profound effects on the host cell DNA methylation machinery and is associated with inflammation in vivo. Our results improve the understanding of cytomegalovirus pathogenesis and open the search for new antiviral therapy targets. These findings may also contribute to the further understanding of mechanisms involved in DNA methylation abnormalities in physiological and pathological conditions.
人类巨细胞病毒（HCMV）是一种普遍存在的疱疹病毒，感染并潜伏在大多数人群中，在免疫功能低下的患者中可能导致致命感染。最近的数据表明，HCMV 编码蛋白与细胞表观遗传机制（如组蛋白乙酰化和去乙酰化）之间存在密切相互作用。在这项研究中，我们使用多种方法研究了 HCMV 感染与不同宿主细胞中的 DNA 甲基化机制之间的相互作用。我们发现，缺乏 DNMT1 和 DNMT3b 甲基转移酶的结肠癌细胞系 HCT-116 容易感染 HCMV-AD169，而野生型细胞则不易感染。用 5-氮杂胞苷处理野生型 HCT-116 细胞可使其对感染敏感。对 HCMV 感染的 MRC-5 成纤维细胞的进一步研究表明，存在显著的全基因组低甲基化，这一现象具有病毒株特异性，并与 DNMT1 和 DNMT3b 从核内重新定位到细胞质有关。DNMT1 的细胞质积累在体外感染的巨噬细胞和炎症性肠病患者组织样本中的上皮细胞中也很明显，同时伴有 HCMV 感染。法昔洛韦（foscavir）治疗感染病毒的成纤维细胞并不影响大多数病毒诱导的核内排除 DNMT1，这表明其依赖于病毒 IE 基因产物。总之，HCMV 感染对宿主细胞的 DNA 甲基化机制产生了深远的影响，并与体内炎症有关。我们的研究结果提高了对巨细胞病毒发病机制的认识，并为寻找新的抗病毒治疗靶点开辟了道路。这些发现还可能有助于进一步了解生理和病理条件下 DNA 甲基化异常的机制。
