Methylation-Mediated Proviral Silencing Is Associated with MeCP2 Recruitment and Localized Histone H3 Deacetylation

doi:10.1128/MCB.21.23.7913-7922.2001

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Molecular and Cellular Biology, December 2001, p. 7913-7922, Vol. 21, No. 23
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.23.7913-7922.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Methylation-Mediated Proviral Silencing Is Associated with MeCP2 Recruitment and Localized Histone H3 Deacetylation

Matthew C. Lorincz,¹ Dirk Schübeler,¹ and Mark Groudine¹^,²^,^*

Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109,¹ and Department of Radiation Oncology, University of Washington School of Medicine, Seattle, Washington 98195²

Received 31 May 2001/Returned for modification 3 August 2001/Accepted 22 August 2001

The majority of 5-methylcytosine in mammalian DNA resides in endogenous transposable elements and is associated with the transcriptionalsilencing of these parasitic elements. Methylation also playsan important role in the silencing of exogenous retroviruses.One of the difficulties inherent in the study of proviral silencingis that the sites in which proviruses randomly integrate influencethe probability of de novo methylation and expression. In orderto compare methylated and unmethylated proviruses at the samegenomic site, we used a recombinase-based targeting approach tointroduce an in vitro methylated or unmethylated Moloney murineleukemia-based provirus in MEL cells. The methylated and unmethylatedstates are maintained in vivo, with the exception of the initiallymethylated proviral enhancer, which becomes demethylated in vivo.Although the enhancer is unmethylated and remodeled, the methylatedprovirus is transcriptionally silent. To further analyze the repressedstate, histone acetylation status was determined by chromatinimmunoprecipitation (ChIP) analyses, which revealed that localizedhistone H3 but not histone H4 hyperacetylation is inversely correlatedwith proviral methylation density. Since members of the methyl-CpGbinding domain (MBD) family of proteins recruit histone deacetylaseactivity, these proteins may play a role in proviral repression.Interestingly, only MBD3 and MeCP2 are expressed in MEL cells.ChIPs with antibodies specific for these proteins revealed thatonly MeCP2 associates with the provirus in a methylation-dependentmanner. Taken together, our results suggest that MeCP2 recruitmentto a methylated provirus is sufficient for transcriptional silencing,despite the presence of a remodeledenhancer.

^* Corresponding author. Mailing address: Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N, A3-025, Seattle, WA 98109.Phone: (206) 667-4497. Fax: (206) 667-5894. E-mail: markg{at}fhcrc.org.

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