title: 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.
authors.affiliation: 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; c.bangham@imperial.ac.uk y-satou@kumamoto-u.ac.jp.
authors.forename: Yorifumi
authors.initials: Y
authors.lastname: Satou
authors.affiliation: 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;
authors.forename: Paola
authors.initials: P
authors.lastname: Miyazato
authors.affiliation: Priority Organization for Innovation and Excellence, Kumamoto University, Kumamoto 860-0811, Japan; Core Research for Evolutionary Science and Technology, Japan Science and Technology Agency, Saitama 332-0012, Japan;
authors.forename: Ko
authors.initials: K
authors.lastname: Ishihara
authors.affiliation: Section of Virology, Division of Infectious Diseases, Imperial College, London W2 1PG, United Kingdom;
authors.forename: Hiroko
authors.initials: H
authors.lastname: Yaguchi
authors.affiliation: Section of Virology, Division of Infectious Diseases, Imperial College, London W2 1PG, United Kingdom;
authors.forename: Anat
authors.initials: A
authors.lastname: Melamed
authors.affiliation: Section of Virology, Division of Infectious Diseases, Imperial College, London W2 1PG, United Kingdom;
authors.forename: Michi
authors.initials: M
authors.lastname: Miura
authors.affiliation: 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;
authors.forename: Asami
authors.initials: A
authors.lastname: Fukuda
authors.affiliation: Cancer Centre, Kumamoto University Hospital, Kumamoto University, Kumamoto 860-0811, Japan;
authors.forename: Kisato
authors.initials: K
authors.lastname: Nosaka
authors.affiliation: Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan.
authors.forename: Takehisa
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Section of Virology, Division of Infectious Diseases, Imperial College, London W2 1PG, United Kingdom;
authors.forename: Aileen G
authors.initials: AG
authors.lastname: Rowan
authors.affiliation: Core Research for Evolutionary Science and Technology, Japan Science and Technology Agency, Saitama 332-0012, Japan; Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan.
authors.forename: Mitsuyoshi
authors.initials: M
authors.lastname: Nakao
authors.affiliation: Section of Virology, Division of Infectious Diseases, Imperial College, London W2 1PG, United Kingdom; c.bangham@imperial.ac.uk y-satou@kumamoto-u.ac.jp.
authors.forename: Charles R M
authors.identifier: http://orcid.org/0000-0003-2624-3599
authors.initials: CR
authors.lastname: Bangham
mesh_terms: D050976:Basic-Leucine Zipper Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D001665:Binding Sites; D000076246:CCCTC-Binding Factor; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D002843:Chromatin / Q000648:ultrastructure; D047369:Chromatin Immunoprecipitation; D016384:Consensus Sequence; D004247:DNA / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D004279:DNA, Viral / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D015967:Gene Expression Regulation, Viral; D015894:Genome, Human; D015490:HTLV-I Infections / Q000235:genetics* / Q000821:virology; D042421:Histone Code; D015368:Human T-lymphotropic virus 1 / Q000235:genetics*; D006801:Humans; D016254:Mutagenesis, Insertional / Q000235:genetics*; D011485:Protein Binding; D011533:Proviruses / Q000235:genetics*; D012097:Repressor Proteins / Q000378:metabolism*; D012191:Retroviridae Proteins / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics*; D016662:Virus Integration / Q000235:genetics*
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D002843:Chromatin; D004279:DNA, Viral; C479751:HBZ protein, human T-cell leukemia virus type I; D012097:Repressor Proteins; D012191:Retroviridae Proteins; D014157:Transcription Factors; D054334:Viral Regulatory and Accessory Proteins; C072343:pX protein, Human T-lymphotropic virus 1; D004247:DNA
keywords: CTCF; HTLV-1; epigenetics; latency; retrovirus