Department of Medicine, Washington University School of Medicine, St Louis, Missouri, United States of America.
Department of Microbiology, Kansai Medical University, Osaka, Japan.
PLoS Pathog. 2021 May 21;17(5):e1009577. doi: 10.1371/journal.ppat.1009577. eCollection 2021 May.
Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus that causes an aggressive T-cell malignancy and a variety of inflammatory conditions. The integrated provirus includes a single binding site for the epigenomic insulator, CCCTC-binding protein (CTCF), but its function remains unclear. In the current study, a mutant virus was examined that eliminates the CTCF-binding site. The mutation did not disrupt the kinetics and levels of virus gene expression, or establishment of or reactivation from latency. However, the mutation disrupted the epigenetic barrier function, resulting in enhanced DNA CpG methylation downstream of the CTCF binding site on both strands of the integrated provirus and H3K4Me3, H3K36Me3, and H3K27Me3 chromatin modifications both up- and downstream of the site. A majority of clonal cell lines infected with wild type HTLV-1 exhibited increased plus strand gene expression with CTCF knockdown, while expression in mutant HTLV-1 clonal lines was unaffected. These findings indicate that CTCF binding regulates HTLV-1 gene expression, DNA and histone methylation in an integration site dependent fashion.
人类 T 细胞白血病病毒 1 型（HTLV-1）是一种逆转录病毒，可引起侵袭性 T 细胞恶性肿瘤和多种炎症性疾病。整合的前病毒包含一个与表观遗传绝缘子 CCCTC 结合蛋白（CTCF）结合的单一结合位点，但它的功能仍不清楚。在本研究中，检查了一种消除 CTCF 结合位点的突变病毒。该突变并没有破坏病毒基因表达的动力学和水平，也没有破坏潜伏期的建立或重新激活。然而，该突变破坏了表观遗传屏障功能，导致整合前病毒双链下游 CTCF 结合位点以及该位点上下游的 H3K4Me3、H3K36Me3 和 H3K27Me3 染色质修饰的 DNA CpG 甲基化增强。大多数感染野生型 HTLV-1 的克隆细胞系在 CTCF 敲低时表现出增强的正链基因表达，而突变型 HTLV-1 克隆系的表达不受影响。这些发现表明，CTCF 结合以整合位点依赖的方式调节 HTLV-1 基因表达、DNA 和组蛋白甲基化。
