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J. Biol. Chem., Vol. 283, Issue 27, 18612-18620, July 4, 2008

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Genomic Matrix Attachment Region and Chromosome Conformation Capture Quantitative Real Time PCR Assays Identify Novel Putative Regulatory Elements at the Imprinted Dlk1/Gtl2 Locus^*

Caroline Braem¹, Bénédicte Recolin, Rebecca C. Rancourt, Christopher Angiolini, Pauline Barthès, Priscillia Branchu, Franck Court, Guy Cathala, Anne C. Ferguson-Smith, and Thierry Forné²

From the Institut de Génétique Moléculaire, UMR 5535 CNRS-Université Montpellier II, IFR 122, 1919, Route de Mende, 34293 Montpellier Cedex 5, France and the Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3DY, United Kingdom

We previously showed that genomic imprinting regulates matrix attachment region activities at the mouse Igf2 (insulin-like growth factor 2) locus and that these activities are functionally linked to neighboring differentially methylated regions (DMRs). Here, we investigate the similarly structured Dlk1/Gtl2 imprinted domain and show that in the mouse liver, the G/C-rich intergenic germ line-derived DMR, a sequence involved in domain-wide imprinting, is highly retained within the nuclear matrix fraction exclusively on the methylated paternal copy, reflecting its differential function on that chromosome. Therefore, not only "classical" A/T-rich matrix attachment region (MAR) sequences but also other important regulatory DNA elements (such as DMRs) can be recovered from genomic MAR assays following a high salt treatment. Interestingly, the recovery of one A/T-rich sequence (MAR4) from the "nuclear matrix" fraction is strongly correlated with gene expression. We show that this element possesses an intrinsic activity that favors transcription, and using chromosome conformation capture quantitative real time PCR assays, we demonstrate that the MAR4 interacts with the intergenic germ line-derived DMR specifically on the paternal allele but not with the Dlk1/Gtl2 promoters. Altogether, our findings shed a new light on gene regulation at this locus.

Received for publication, March 7, 2008 , and in revised form, April 17, 2008.

^* This work was supported by Association pour la Recherche contre le Cancer Contract 4868, "GIS Longévité" Contract GISLO401, Agence Nationale de la Recherche Grant ANR-07-BLAN-0052-02 (to T. F.), and funds from the Centre National de la Recherche Scientifique. This work was also supported by Cancer Research-United Kingdom, the Bill and Melinda Gates Trust (Cambridge), and European Union Framework Program 6. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables 1 and 2.

¹ Supported by Association pour la Recherche contre le Cancer Fellowship JR/MLD/MDV-P05/2 and P06/2.

² To whom correspondence should be addressed: IGMM, UMR5535 CNRS-UMII, IFR122, 1919, Route de Mende, 34293 Montpellier Cedex 5, France. Tel.: 33-467-61-36-84; Fax: 33-467-04-02-31; E-mail: forne{at}igmm.cnrs.fr.

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