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J. Biol. Chem., Vol. 283, Issue 20, 13611-13626, May 16, 2008

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Histone Code Modifications Repress Glucose Transporter 4 Expression in the Intrauterine Growth-restricted Offspring^*

From the Division of Neonatology and Developmental Biology and the Neonatal Research Center, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, California 90095-1752

We examined transcriptional and epigenetic mechanism(s) behind diminished skeletal muscle GLUT4 mRNA in intrauterine growth-restricted (IUGR) female rat offspring. An increase in MEF2D (inhibitor) with a decline in MEF2A (activator) and MyoD (co-activator) binding to the glut4 promoter in IUGR versus control was observed. The functional role of MEF2/MyoD-binding sites and neighboring three CpG clusters in glut4 gene transcription was confirmed in C2C12 muscle cells. No differential methylation of these three and other CpG clusters in the glut4 promoter occurred. DNA methyltransferase 1 (DNMT1) in postnatal, DNMT3a, and DNMT3b in adult was differentially recruited with increased MeCP2 (methyl CpG-binding protein) concentrations to bind the IUGR glut4 gene. Covalent modifications of the histone (H) code consisted of H3.K14 de-acetylation by recruitment of histone deacetylase (HDAC) 1 and enhanced association of HDAC4 enzymes. This set the stage for Suv39H1 methylase-mediated di-methylation of H3.K9 and increased recruitment of heterochromatin protein 1, which partially inactivates postnatal and adult IUGR glut4 gene transcription. Further increased interactions in the adult IUGR between DNMT3a/DNMT3b and HDAC1 and MEF2D and HDAC1/HDAC4 and decreased association between MyoD and MEF2A existed. We conclude that epigenetic mechanisms consisting of histone code modifications repress skeletal muscle glut4 transcription in the postnatal period and persist in the adult female IUGR offspring.

Received for publication, January 7, 2008 , and in revised form, February 21, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants HD 41230, HD 25024, HD 46979, and HD 33997. 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 1–4 and Figs. S.1–S.5.

¹ To whom correspondence should be addressed: 10833 Le Conte Ave., MDCC-B2-375, UCLA, Los Angeles, CA 90095-1752. Tel.: 310-825-9436; Fax: 310-267-0517; E-mail: sdevaskar{at}mednet.ucla.edu.

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