The undermethylated state of a CpG island region in igf2 transgenes is dependent on the H19 enhancers.
CpG islands are GC-rich regions located in the promoter regions of housekeeping genes and many tissue-specific genes. While most CpG islands are normally unmethylated, island methylation can occur and is associated with silencing of the corresponding gene. Experiments with transgenic mice and DNA transfection in pluripotential embryonic cells have led to the conclusion that the information required for protecting the islands from methylation is contained within the CpG islands themselves and have identified Sp1 binding sites as an important element in establishing and/or maintaining the methylation-free state of CpG islands. To examine the generality of these observations, we analyzed the methylation of one of the mouse Igf2 CpG islands and its flanks in transgenic mice. We observed that the undermethylated state of this region is dependent on the presence of a separate cis-regulatory element, the H19 enhancers. These tissue-specific enhancers had a ubiquitous, non-tissue-specific effect on island region methylation. Structural alterations outside of the island and these enhancers also affected this region's methylation. These findings indicate that the methylation of some CpG island-containing regions is more sensitive than previously believed to the activity of distant cis-regulatory elements and to structural alterations in nonisland sequences in cis.
Wise
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Department of Human Genetics, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, 10314, USA.
Pravtcheva
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D000818:Animals; D018899:CpG Islands / Q000187:drug effects*; D019175:DNA Methylation; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D016147:Genes, Tumor Suppressor; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D007763:Lac Operon / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics; D009124:Muscle Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D015183:Restriction Mapping; D019076:Transgenes
C094335:H19 long non-coding RNA; D009124:Muscle Proteins; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D007335:Insulin-Like Growth Factor II