CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/Igf2 locus

Amy T. Hark, Christopher J. Schoenherr, David J. Katz, Robert S. Ingram, John M. Levorse, Shirley M. Tilghman

Research output: Contribution to journalArticle

1122 Scopus citations

Abstract

The Insulin-like growth factor 2 (Igf2) and H19 genes are imprinted, resulting in silencing of the maternal and paternal alleles, respectively. This event is dependent upon an imprinted-control region two kilobases upstream of H19 (refs 1,2). On the paternal chromosome this element is methylated and required for the silencing of H19 (refs 2-4). On the maternal chromosome the region is unmethylated and required for silencing of the Igf2 gene 90 kilobases upstream. We have proposed that the unmethylated imprinted- control region acts as a chromatin boundary that blocks the interaction of Igf2 with enhancers that lie 3' of H19 (refs 5,6). This enhancer-blocking activity would then be lost when the region was methylated, thereby allowing expression of Igf2 paternally. Here we show, using transgenic mice and tissue culture, that the unmethylated imprinted-control regions from mouse and human H19 exhibit enhancer-blocking activity. Furthermore, we show that CTCF, a zinc finger protein implicated in vertebrate boundary function, binds to several sites in the unmethylated imprinted-control region that are essential for enhancer blocking. Consistent with our model, CTCF binding is abolished by DNA methylation. This is the first example, to our knowledge, of a regulated chromatin boundary in vertebrates.

Original languageEnglish (US)
Pages (from-to)486-489
Number of pages4
JournalNature
Volume405
Issue number6785
DOIs
StatePublished - May 25 2000

All Science Journal Classification (ASJC) codes

  • General

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    Hark, A. T., Schoenherr, C. J., Katz, D. J., Ingram, R. S., Levorse, J. M., & Tilghman, S. M. (2000). CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/Igf2 locus. Nature, 405(6785), 486-489. https://doi.org/10.1038/35013106