DNA methylation and chromosome instability in lymphoblastoid cell lines

In order to gain more insight into the relationships between DNA methylatio n and genome stability, chromosomal and molecular evolutions of four Epstei n-Barr virus-transformed human lymphoblastoid cell lines were followed in c ulture for more than 2 yr. The four cell lines underwent early, strong over all demethylation of the genome. The classical satellite-rich, heterochroma tic juxtacentromeric regions of chromosomes 1, 9, and 16 and the distal par t of the long arm of the Y chromosome displayed specific behavior with time in culture. In two cell lines, they underwent a strong demethylation, invo lving successively chromosomes Y, 9, 16, and 1, whereas in the two other ce ll lines, they remained heavily methylated. For classical satellite 2-rich heterochromatic regions of chromosomes 1 and 16, a direct relationship coul d be established between their demethylation, their undercondensation at me taphase, and their involvement in non-clonal rearrangements. Unstable sites distributed along the whole chromosomes were found only when the heterochr omatic regions of chromosomes 1 and 16 were unstable. The classical satelli te 3-rich heterochromatic region of chromosomes 9 and Y, despite their stro ng demethylation, remained condensed and stable. Genome demethylation and c hromosome instability could not be related to variations in mRNA amounts of the DNA methyltransferases DNMT1, DNMT3A, and DNMT3B and DNA demethylase. These data suggest that the influence of DNA demethylation on chromosome st ability is modulated by a sequence-specific chromatin structure. Copyright (C) 2000 S. Karger AG, Basel.