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(Received for publication, June 10, 1996, and in revised form, October 23, 1996)
From the Sir Donald and Lady Trescowthick Research Laboratories,
Peter MacCallum Cancer Institute, Locked Bag No. 1, A'Beckett
Street, Melbourne, Victoria 3000, Australia
We have investigated the function and
sequence specificity of DNA methylation in the hypermethylated CpG
island promoter region of the endogenous human LINE-1 (L1)
retrotransposon family. In nontransformed human embryonic fibroblasts,
inhibition of DNA methylation with 5-azadeoxycytidine induced a greater
than 4-fold increase in transcription from potentially functional L1
elements without increasing the transcription level of the majority of degenerate elements, implicating hypermethylation in the repression of
L1 activity. Using bisulfite genomic sequencing to assess the pattern
of methylation in a subset of nondegenerate L1 elements, we found 29 sites within a 460-base pair region of the noncoding (top) DNA strand
of the L1 promoter in which cytosine methylation was maintained with
high efficiency. Of these, 25 were at CG dinucleotides and four were in
non-CG sites. When the methylation sites were analyzed for the
complementary (bottom) strand, the only highly conserved sites of
methylation were in CG dinucleotides. Several of these sites of CG
methylation in the bottom (coding) strand were at positions where top
(noncoding) strand-derived sequences were unmethylated, suggesting that
these sites might be maintained in a hemi-methylated state. Hence,
there is a subset of human L1 elements in which methylation is
efficiently maintained in asymmetric non-CG sites and further that this
non-CG methylation may be part of a wider phenomenon involving
hemi-methylation at CG dinucleotides. Maintenance of asymmetric
methylation at non-CG sites (and possibly at hemi-methylated CG
dinucleotides) could be through a novel DNA methyltransferase activity.
Alternatively, the promoter region of L1 elements may be induced by
factor binding to form some type of secondary structure that presents
as a highly efficient substrate for de novo
methylation.
Volume 272, Number 12,
Issue of March 21, 1997
pp. 7810-7816
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
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