Methylation of L1Hs promoters is lower on the inactive X, has a tendency of being higher on autosomes in smaller genomes and shows inter-individual variability at some loci

Abstract

LINE-1 repeats account for ∼17% of the human genome. Little is known about their individual methylation patterns, because their repetitive, almost identical sequences make them difficult to be individually targeted. Here, we used bisulfite conversion to study methylation at individual LINE-1 repeats. The loci studied included 39 X-linked loci and 5 autosomal loci. On the X chromosome in women, we found statistically significant less methylation at almost all L1Hs compared with men. Methylation at L1P and L1M did not correlate with the inactivation status of the host DNA, while the majority of L1Hs that were possible to be studied lie in inactivated regions. To investigate whether the male–female differences at L1Hs on the X are linked to the inactivation process itself rather than to a mere influence of gender, we analyzed six of the L1Hs loci on the X chromosome in Turners and Klinefelters which have female and male phenotype, respectively, but with reversed number of X chromosomes. We could confirm that all samples with two X chromosomes are hypomethylated at the L1Hs loci. Therefore, the inactive X is hypomethylated at L1Hs; the latter could play an exclusive role in the X chromosome inactivation process. At autosomal L1Hs, methylation levels showed a correlation tendency between methylation level and genome size, with higher methylation observed at most loci in individuals with one X chromosome and the lowest in XXY individuals. In summary, loci-specific LINE-1 methylation levels show considerable plasticity and depend on genomic position and constitution.

Retrotransposition creates sloping shores: a graded influence of hypomethylated CpG islands on flanking CpG sites

“…Consistent with this hypothesis, significant interindividual variability in DNA methylation has been observed for discrete Alu and L1 elements (Sandovici et al 2005;Singer et al 2012). In addition, monoallelically expressed genes are frequently flanked by high densities of evolutionarily recent L1s but low densities of SINEs (Greally 2002;Allen et al 2003), implicating a role of differential epigenetic modification of retrotransposon subfamilies in controlling neighboring gene expression.…”

Is There a Link Between Genome-Wide Hypomethylation in Blood and Cancer Risk?

“…Age is a strong modifier of DNA methylation for some genes (12,100), and is the biggest risk factor for most cancers, therefore, adjustment for age is essential (12, 100). L1 methylation is significantly lower in females than males (80,101,102), probably because of differences in the X and Y chromosomes (103), therefore, population studies investigating genome-wide DNA methylation must be stratified by gender (79,80,101,104). Whereas gender may represent a confounding factor for some of the included studies (72,85), statistical adjustment may have helped to reduce this bias.…”

“…L1 pyrosequencing, however, displays little technical variation (108), and it will be important to determine whether measures of 5meC are as technically reproducible. L1 elements are differentially methylated at different genomic loci (50,103,111), and at different CpG loci within the L1 consensus sequence (98), therefore, assays preferentially amplifying different L1 elements or measuring methylation at different CpG sites may produce inconsistent results.…”

LINE-1 and Alu Methylation Patterns in Lymph Node Metastases of Head and Neck Cancers

“…Each LINE-1 locus has a distinct methylation level and pattern (Phokaew, 2008;Singer, 2012). To improve the efficiency of detecting cancer DNA and to measure the overall methylation level, we recently classified LINE1s into 4 groups based on the methylation statuses of 2 CpG dinucleotides in each LINE-1 sequence.…”