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J. Biol. Chem., Vol. 283, Issue 26, 18187-18197, June 27, 2008

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 283/26/18187    most recent M803330200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Mager, G. M. Articles by Svaren, J. PubMed PubMed Citation Articles by Mager, G. M. Articles by Svaren, J. Social Bookmarking                      What's this?

Active Gene Repression by the Egr2·NAB Complex during Peripheral Nerve Myelination^*

Gennifer M. Mager¹, Rebecca M. Ward, Rajini Srinivasan, Sung-Wook Jang^¶, Lawrence Wrabetz^||, and John Svaren^**2

From the Molecular and Cellular Pharmacology Training Program, Department of Comparative Biosciences, ^¶Graduate Program in Cellular and Molecular Biology, and ^**Waisman Center, University of Wisconsin, Madison, Wisconsin 53706 and the ^||Dipartimento di Ricerca Biologica e Technologica, San Raffaele Scientific Institute, Milan 20132, Italy

The Egr2/Krox20 transactivator is required for activation of many myelin-associated genes during peripheral nerve myelination by Schwann cells. However, recent work has indicated that Egr2 not only activates genes required for peripheral nerve myelination but may also be involved in gene repression. The NAB (NGFI-A/Egr-binding) corepressors interact with Egr2 and are required for proper coordination of myelin formation. Therefore, NAB proteins could mediate repression of some Egr2 target genes, although direct repression by Egr2 or NAB proteins during myelination has not been demonstrated. To define the physiological role of NAB corepression in gene repression by Egr2, we tested whether the Egr2·NAB complex directly repressed specific target genes. A screen for NAB-regulated genes identified several (including Id2, Id4, and Rad) that declined during the course of peripheral nerve myelination. In vivo chromatin immunoprecipitation analysis of the myelinating sciatic nerve was used to show developmental association of both Egr2 and NAB2 on the Id2, Id4, and Rad promoters as they were repressed during the myelination process. In addition, NAB2 represses transcription by interaction with the chromodomain helicase DNA-binding protein 4 (CHD4) subunit of the nucleosome remodeling and deacetylase chromatin remodeling complex, and we demonstrate that CHD4 occupies NAB-repressed promoters in a developmentally regulated manner in vivo. These results illustrate a novel aspect of genetic regulation of peripheral nerve myelination by showing that Egr2 directly represses genes during myelination in conjunction with NAB corepressors. Furthermore, repression of Id2 was found to augment activation of Mpz (myelin protein zero) expression.

Received for publication, May 1, 2008

This paper is dedicated to the memory of Brad Sevetson.

^* This work was supported, in whole or in part, by National Institutes of Health Grant HD41590 (to J. S.) and National Institutes of Health Core Grant P30 HD03352 from NICHD (to the Waisman Center). This work was also supported by a grant from Telethon, Italy (to L. W.). 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 Table 1.

¹ Supported by National Institutes of Health Training Grant T32 GM08688.

² To whom correspondence should be addressed: 2015 Linden Dr., University of Wisconsin, Madison, WI 53706. Tel.: 608-263-4246; Fax: 608-263-3926; E-mail: jpsvaren{at}wisc.edu.

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