A METHYLATED CPG ISLAND 3' IN THE APOLIPOPROTEIN-E GENE DOES NOT REPRESS ITS TRANSCRIPTION

CpG islands are always associated with the 5' end of housekeeping gene s, covering their promoters and transcription start sites. CpG islands associated with genes of limited expression are less uniformly locali zed; the genes for apolipoprotein-E and -AI contain CpG islands corres ponding to their last exons. As expected, the CpG island in the apo-AI gene is unmethylated in DNA from all tissues analyzed, expressing as well as non-expressing apolipoprotein-AI. In contrast, the apo-E CpG i sland is methylated in DNA from all tissues analyzed except sperm. The apo-E gene is transcribed in many tissues and is not repressed by thi s methylation. This establishes a functional difference between 5' and 3' CpG islands, because methylation of the former invariably leads to transcriptional repression. A similar methylation pattern was seen in the rat apo-E gene, which implies that this pattern probably was esta blished before the divergence of rodents and primates. The numerous hu man apo-E alleles resulting from CpG to TpG/CpA mutations in the CpG i sland (i.e. deamination of methylated cytosine to thymine) suggest tha t this island is less protected from methylation in germ line than typ ical CpG islands.