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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

X inactivation-specific methylation of LINE-1 elements by DNMT3B: implications for the Lyon repeat hypothesis.

Lyon has proposed that long interspersed nuclear element 1 (LINE-1 or L1) repeats may be mediators for the spread of X chromosome inactivation. Cells from ICF patients who are deficient in one of the DNA methyltransferases, DNMT3B, provide an opportunity to explore and refine this hypothesis. Southern blot and bisulfite methylation analyses indicate that, in normal somatic cells, X-linked L1s are hypermethylated on both the active and inactive X chromosomes. In contrast, ICF syndrome cells with DNMT3B mutations have L1s that are hypomethylated on the inactive X, but not on the active X or autosomes. The DNMT3B methyltransferase, therefore, is required for methylation of L1 CpG islands on the inactive X, whereas methylation of the corresponding L1 loci on the active X, as well as most autosomal L1s, is accomplished by another DNA methyltransferase. This unique phenomenon of identical allelic modifications by different enzymes has not been previously observed. Apart from CpG island methylation, the ICF inactive X is basically normal in that it forms a Barr body, is associated with XIST RNA, mostly replicates late, and its X-inactivated genes are mostly silent. Because the unmethylated state of the ICF inactive X L1s probably reflects their methylation status at the time of X inactivation, these data suggest that unmethylated L1 elements, but not methylated L1s, may have a role in the spreading of X chromosome inactivation.[1]


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