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Nucleic Acids Research Advance Access originally published online on December 15, 2008
Nucleic Acids Research 2009 37(3):793-803; doi:10.1093/nar/gkn985
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Nucleic Acids Research, 2009, Vol. 37, No. 3 793-803
© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Gene regulation, Chromatin and Epigenetics

The Igf2/H19 imprinting control region exhibits sequence-specific and cell-type-dependent DNA methylation-mediated repression

Yinming Chen, Amrita Dhupelia and Christopher J. Schoenherr*

Department of Cell and Developmental Biology, University of Illinois, Urbana-Champaign, Urbana, IL 61801, USA

*To whom correspondence should be addressed. Tel: +1 217 265 8036; Fax: +1 217 244 1648; Email: schoenhe{at}life.uiuc.edu

Received August 25, 2008. Revised November 20, 2008. Accepted November 21, 2008.

Methylation of CpGs is generally thought to repress transcription without significant influence from the sequence surrounding the methylated dinucleotides. Using the mouse Igf2/H19 imprinting control region (ICR), Igf2r differentially methylated region 2 (DMR2) and bacterial sequences, we addressed how methylation-dependent repression (MDR) from a distance varies with CpG number, density and surrounding sequence. In stably transfected F9 cells, the methylated ICR repressed expression from a CpG-free reporter plasmid more than 1000-fold compared with its unmethylated control. A segment of pBluescript, with a CpG number equal to the ICR's but with a higher density, repressed expression only 70-fold when methylated. A bacteriophage lambda fragment and the Igf2r DMR2 showed minimal MDR activity, despite having CpG numbers and densities similar to or greater than the ICR. By rearranging or deleting CpGs, we identified CpGs associated with three CTCF sites in the ICR that are necessary and sufficient for sequence-specific MDR. In contrast to F9 cells, the methylated ICR and pBS fragments exhibited only 3-fold reporter repression in Hela cells and none in Cos7. Our results show that the strength of MDR from a distance can vary a 1000-fold between different cell types and depends on the sequence surrounding the methylated CpGs, but does not necessarily increase with CpG number or density.


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