The retrovirus HTLV-1 inserts an ectopic CTCF-binding site into the human genome

Abstract

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.retrovirus | latency | epigenetics | HTLV-1 | CTCF

Systematic identification and characterization of regulatory elements derived from human endogenous retroviruses

“…Although the role of retroviral internal sequences in transcription remains unclear, it is known that an internal sequence in Human T-cell Leukemia Virus Type 1 (HTLV-1) contains a CTCF-binding site functioning as an insulator [57]. In the present study, we found that a substantial fraction of HSREs was present in the internal sequences, and the most frequently observed HSRE in the internal sequences was the CTCF-binding site (S5I Fig).…”

“…In the present study, we found that a substantial fraction of HSREs was present in the internal sequences, and the most frequently observed HSRE in the internal sequences was the CTCF-binding site (S5I Fig). These findings suggest that regulatory elements, particularly CTCF-binding sites, would be present in the internal sequences of retroviruses, including HERVs, more than previously considered [38, 57]. Further investigation is needed for clarifying the role of retroviral internal sequences in transcriptional modulation.…”

Application of targeted enrichment to next-generation sequencing of retroviruses integrated into the host human genome

“…We recently reported that CTCF bound to HTLV-1 provirus and defined a border in the epigenetic modifications profile8. In this previous study, we sequenced ChIP-seq libraries without enrichment.…”

Epigenetics and Genetics of Viral Latency

“…Recent studies with HPV reveal that CTCF regulates the alternative splicing of viral RNA transcripts (Paris et al, 2015), as well as the recruitment of the cohesin subunit SMC1 required for viral genome amplification. CTCF can also bind to the proviral genome of the retrovirus HTLV-1 to regulate RNA splicing, epigenetic boundaries, and the antisense transcription of the viral HBZ gene, necessary for clonal persistence (Satou et al, 2016). Thus, CTCF may facilitate viral chromatin structure, RNA polymerase II programming, and recombination-based genome amplification essential for maintaining latent viral genomes.…”