Agricultural Bioinformatics Key Laboratory of Hubei Province, Hubei Engineering Technology Research Center of Agricultural Big Data, College of Informatics, Huazhong Agricultural University, Wuhan, China.
School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China.
Front Immunol. 2020 Sep 10;11:2131. doi: 10.3389/fimmu.2020.02131. eCollection 2020.
Host genomic alterations are closely related to dysfunction of CD4 T lymphocytes in the HIV-host interplay. However, the roles of aberrant DNA methylation and gene expression in the response to HIV infection are not fully understood. We investigated the genome-wide DNA methylation and transcriptomic profiles in two HIV-infected T lymphocyte cell lines using high-throughput sequencing. Based on DNA methylation data, we identified 3,060 hypomethylated differentially methylated regions (DMRs) and 2,659 hypermethylated DMRs in HIV-infected cells. Transcription-factor-binding motifs were significantly associated with methylation alterations, suggesting that DNA methylation modulates gene expression by affecting the binding to transcription factors during HIV infection. In support of this hypothesis, genes with promoters overlapping with DMRs were enriched in the biological function related to transcription factor activities. Furthermore, the analysis of gene expression data identified 1,633 upregulated genes and 2,142 downregulated genes on average in HIV-infected cells. These differentially expressed genes (DEGs) were significantly enriched in apoptosis-related pathways. Our results suggest alternative splicing as an additional mechanism that may contribute to T-cell apoptosis during HIV infection. We also demonstrated a genome-scale correlation between DNA methylation and gene expression in HIV-infected cells. We identified 831 genes with alterations in both DNA methylation and gene expression, which were enriched in apoptosis. Our results were validated using various experimental methods. In addition, consistent with our results, a luciferase assay showed that the activity of the and promoters was significantly decreased in the presence of HIV proteins, indicating the potential of these genes as genetic markers of HIV infection. Our results suggest important roles for DNA methylation and gene expression regulation in T-cell apoptosis during HIV infection. We propose a list of novel genes related to these processes for further investigation. This study also provides a comprehensive characterization of changes occurring at the transcriptional and epigenetic levels in T cells in response to HIV infection.
宿主基因组的改变与 HIV 宿主相互作用中 CD4 T 淋巴细胞功能障碍密切相关。然而，异常的 DNA 甲基化和基因表达在 HIV 感染反应中的作用尚不完全清楚。我们使用高通量测序研究了两种 HIV 感染的 T 淋巴细胞系的全基因组 DNA 甲基化和转录组谱。基于 DNA 甲基化数据，我们在 HIV 感染的细胞中鉴定出 3060 个低甲基化差异甲基化区域（DMR）和 2659 个高甲基化 DMR。转录因子结合基序与甲基化改变显著相关，表明 DNA 甲基化通过影响 HIV 感染过程中与转录因子的结合来调节基因表达。支持这一假设，与 DMR 重叠的启动子的基因富集在与转录因子活性相关的生物学功能中。此外，对基因表达数据的分析表明，HIV 感染的细胞中平均有 1633 个上调基因和 2142 个下调基因。这些差异表达基因（DEGs）显著富集在凋亡相关途径中。我们的结果表明，选择性剪接可能是 HIV 感染过程中 T 细胞凋亡的另一种机制。我们还证明了 HIV 感染细胞中 DNA 甲基化和基因表达之间存在全基因组相关性。我们鉴定出 831 个在 DNA 甲基化和基因表达中都发生改变的基因，这些基因在凋亡中富集。我们的结果使用各种实验方法进行了验证。此外，与我们的结果一致，荧光素酶测定表明，在存在 HIV 蛋白的情况下，和 启动子的活性显著降低，表明这些基因作为 HIV 感染遗传标记的潜力。我们的结果表明，DNA 甲基化和基因表达调控在 HIV 感染过程中的 T 细胞凋亡中起着重要作用。我们提出了一组与这些过程相关的新基因，以供进一步研究。本研究还提供了 HIV 感染后 T 细胞在转录和表观遗传水平上发生变化的全面特征。
