Department of Infectious Diseases, Faculty of Medicine, Imperial College London, London, United Kingdom.
PLoS Pathog. 2024 Mar 1;20(3):e1011716. doi: 10.1371/journal.ppat.1011716. eCollection 2024 Mar.
A typical HTLV-1-infected individual carries >104 different HTLV-1-infected T cell clones, each with a single-copy provirus integrated in a unique genomic site. We previously showed that the HTLV-1 provirus causes aberrant transcription in the flanking host genome and, by binding the chromatin architectural protein CTCF, forms abnormal chromatin loops with the host genome. However, it remained unknown whether these effects were exerted simply by the presence of the provirus or were induced by its transcription. To answer this question, we sorted HTLV-1-infected T-cell clones into cells positive or negative for proviral plus-strand expression, and then quantified host and provirus transcription using RNA-seq, and chromatin looping using quantitative chromosome conformation capture (q4C), in each cell population. We found that proviral plus-strand transcription induces aberrant transcription and splicing in the flanking genome but suppresses aberrant chromatin loop formation with the nearby host chromatin. Reducing provirus-induced host transcription with an inhibitor of transcriptional elongation allows recovery of chromatin loops in the plus-strand-expressing population. We conclude that aberrant host transcription induced by proviral expression causes temporary, reversible disruption of chromatin looping in the vicinity of the provirus.
一般来说，单个 HTLV-1 感染者携带超过 104 种不同的 HTLV-1 感染 T 细胞克隆，每个克隆的单个拷贝前病毒整合在独特的基因组位置。我们之前曾表明，HTLV-1 前病毒导致侧翼宿主基因组的异常转录，并通过与染色质结构蛋白 CTCF 结合，形成与宿主基因组的异常染色质环。然而，尚不清楚这些影响是仅仅由前病毒的存在引起的，还是由其转录引起的。为了回答这个问题，我们将 HTLV-1 感染的 T 细胞克隆分为前病毒正链表达阳性或阴性的细胞，并使用 RNA-seq 分别在每个细胞群体中定量检测宿主和前病毒转录，以及使用定量染色体构象捕获（q4C）定量检测染色质环。我们发现，前病毒正链转录诱导侧翼基因组中的异常转录和剪接，但抑制附近宿主染色质的异常染色质环形成。用转录延伸抑制剂降低前病毒诱导的宿主转录，可以恢复正链表达群体中的染色质环。我们得出结论，前病毒表达诱导的异常宿主转录导致前病毒附近染色质环的暂时、可逆破坏。
