Satou Yorifumi, Miyazato Paola, Ishihara Ko, Yaguchi Hiroko, Melamed Anat, Miura Michi, Fukuda Asami, Nosaka Kisato, Watanabe Takehisa, Rowan Aileen G, Nakao Mitsuyoshi, Bangham Charles R M
Section of Virology, Division of Infectious Diseases, Imperial College, London W2 1PG, United Kingdom; Centre for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan; Priority Organization for Innovation and Excellence, Kumamoto University, Kumamoto 860-0811, Japan; International Research Centre for Medical Science, Kumamoto University, Kumamoto 860-0811, Japan; Core Research for Evolutionary Science and Technology, Japan Science and Technology Agency, Saitama 332-0012, Japan;
Centre for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan; Priority Organization for Innovation and Excellence, Kumamoto University, Kumamoto 860-0811, Japan; International Research Centre for Medical Science, Kumamoto University, Kumamoto 860-0811, Japan;
Proc Natl Acad Sci U S A. 2016 Mar 15;113(11):3054-9. doi: 10.1073/pnas.1423199113. Epub 2016 Feb 29.
Human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus that causes malignant and inflammatory diseases in ∼10% of infected people. A typical host has between 10(4) and 10(5) clones of HTLV-1-infected T lymphocytes, each clone distinguished by the genomic integration site of the single-copy HTLV-1 provirus. The HTLV-1 bZIP (HBZ) factor gene is constitutively expressed from the minus strand of the provirus, whereas plus-strand expression, required for viral propagation to uninfected cells, is suppressed or intermittent in vivo, allowing escape from host immune surveillance. It remains unknown what regulates this pattern of proviral transcription and latency. Here, we show that CTCF, a key regulator of chromatin structure and function, binds to the provirus at a sharp border in epigenetic modifications in the pX region of the HTLV-1 provirus in T cells naturally infected with HTLV-1. CTCF is a zinc-finger protein that binds to an insulator region in genomic DNA and plays a fundamental role in controlling higher order chromatin structure and gene expression in vertebrate cells. We show that CTCF bound to HTLV-1 acts as an enhancer blocker, regulates HTLV-1 mRNA splicing, and forms long-distance interactions with flanking host chromatin. CTCF-binding sites (CTCF-BSs) have been propagated throughout the genome by transposons in certain primate lineages, but CTCF binding has not previously been described in present-day exogenous retroviruses. The presence of an ectopic CTCF-BS introduced by the retrovirus in tens of thousands of genomic locations has the potential to cause widespread abnormalities in host cell chromatin structure and gene expression.
人类嗜T淋巴细胞病毒1型（HTLV-1）是一种逆转录病毒，约10%的感染者会因此患上恶性和炎症性疾病。典型宿主拥有10⁴至10⁵个感染HTLV-1的T淋巴细胞克隆，每个克隆由单拷贝HTLV-1前病毒的基因组整合位点区分。HTLV-1碱性亮氨酸拉链（HBZ）因子基因由前病毒的负链组成性表达，而病毒传播至未感染细胞所需的正链表达在体内受到抑制或呈间歇性，从而逃避免疫监视。目前尚不清楚是什么调节这种前病毒转录和潜伏模式。在此，我们表明，染色质结构和功能的关键调节因子CTCF在自然感染HTLV-1的T细胞中，于HTLV-1前病毒pX区域的表观遗传修饰的一个清晰边界处与前病毒结合。CTCF是一种锌指蛋白，它与基因组DNA中的绝缘子区域结合，在控制脊椎动物细胞的高阶染色质结构和基因表达中起重要作用。我们发现，与HTLV-1结合的CTCF起到增强子阻断剂的作用，调节HTLV-1 mRNA剪接，并与侧翼宿主染色质形成长距离相互作用。在某些灵长类谱系中，转座子已使CTCF结合位点（CTCF-BS）在整个基因组中扩散，但此前尚未在现存的外源性逆转录病毒中描述过CTCF结合情况。逆转录病毒在数以万计的基因组位置引入的异位CTCF-BS有可能导致宿主细胞染色质结构和基因表达出现广泛异常。
