The retrovirus HTLV-1 inserts an ectopic CTCF-binding site into the human genome
File(s)
Accepted version
Author(s)
Type
Journal Article
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
HBZ
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 funda-
mental 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 have been propagated through-
out 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 binding
site 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.
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
HBZ
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 funda-
mental 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 have been propagated through-
out 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 binding
site 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.
Date Issued
2016-03-15
Date Acceptance
2016-02-01
Citation
Proceedings of the National Academy of Sciences of the United States of America, 2016, 113 (11), pp.3054-3059
ISSN
0027-8424
Publisher
National Academy of Sciences
Start Page
3054
End Page
3059
Journal / Book Title
Proceedings of the National Academy of Sciences of the United States of America
Volume
113
Issue
11
Copyright Statement
© 2016 National Academy of Sciences. This paper has been accepted for publication in Proceedings of the National Academy of Sciences and is under embargo until published.
Sponsor
Medical Research Council (MRC)
Wellcome Trust
Grant Number
MR/K019090/1
100291/Z/12/Z
Subjects
MD Multidisciplinary
Publication Status
Published
Date Publish Online
2016-02-29