Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
EBioMedicine. 2019 May;43:127-137. doi: 10.1016/j.ebiom.2019.04.045. Epub 2019 May 2.
Investigations into the function of non-promoter DNA methylation have yielded new insights into the epigenetic regulation of gene expression. However, integrated genome-wide non-promoter DNA methylation and gene expression analyses across a wide number of tumour types and corresponding normal tissues have not been performed.
To investigate the impact of non-promoter DNA methylation on cancer pathogenesis, we performed a large-scale analysis of gene expression and DNA methylation profiles, finding enrichment in the 3'UTR DNA methylation positively correlated with gene expression. Filtering for genes in which 3'UTR DNA methylation strongly correlated with gene expression yielded a list of genes enriched for functions involving T cell activation.
The important immune checkpoint gene Havcr2 showed a substantial increase in 3'UTR DNA methylation upon T cell activation and subsequent upregulation of gene expression in mice. Furthermore, this increase in Havcr2 gene expression was abrogated by treatment with decitabine.
These findings indicate that the 3'UTR is a functionally relevant DNA methylation site. Additionally, we show a potential novel mechanism of HAVCR2 regulation in T cells, providing new insights for modulating immune checkpoint blockade.
对非启动子 DNA 甲基化功能的研究为基因表达的表观遗传调控提供了新的见解。然而，针对大量肿瘤类型及相应正常组织，尚未进行全基因组范围的非启动子 DNA 甲基化和基因表达综合分析。
为了研究非启动子 DNA 甲基化对癌症发病机制的影响，我们对基因表达和 DNA 甲基化谱进行了大规模分析，发现 3'UTR DNA 甲基化与基因表达呈正相关的富集。对与基因表达强相关的 3'UTR DNA 甲基化进行基因过滤，得到了一组富集于涉及 T 细胞激活功能的基因列表。
重要的免疫检查点基因 Havcr2 在 T 细胞激活后，其 3'UTR DNA 甲基化显著增加，随后在小鼠中的基因表达上调。此外，用地西他滨处理可消除 Havcr2 基因表达的这种增加。
这些发现表明 3'UTR 是一个具有功能相关性的 DNA 甲基化位点。此外，我们展示了 T 细胞中 HAVCR2 调节的一种潜在新机制，为调节免疫检查点阻断提供了新的见解。
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