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Molecular and Cellular Biology, January 2008, p. 215-226, Vol. 28, No. 1
0270-7306/08/$08.00+0     doi:10.1128/MCB.01073-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

LSH Cooperates with DNA Methyltransferases To Repress Transcription{triangledown} ,{dagger}

Kevin Myant and Irina Stancheva*

Wellcome Trust Centre for Cell Biology, University of Edinburgh, Michael Swann Building, Mayfield Road, Edinburgh EH9 3JR, United Kingdom

Received 17 June 2007/ Returned for modification 16 August 2007/ Accepted 11 October 2007

LSH, a protein related to the SNF2 family of chromatin-remodeling ATPases, is required for efficient DNA methylation in mammals. How LSH functions to support DNA methylation and whether it associates with a large protein complex containing DNA methyltransferase (DNMT) enzymes is currently unclear. Here we show that, unlike many other chromatin-remodeling ATPases, native LSH is present mostly as a monomeric protein in nuclear extracts of mammalian cells and cannot be detected in a large multisubunit complex. However, when targeted to a promoter of a reporter gene, LSH acts as an efficient transcriptional repressor. Using this as an assay to identify proteins that are required for LSH-mediated repression we found that LSH cooperates with the DNMTs DNMT1 and DNMT3B and with the histone deacetylases (HDACs) HDAC1 and HDAC2 to silence transcription. We show that transcriptional repression by LSH and interactions with HDACs are lost in DNMT1 and DNMT3B knockout cells but that the enzymatic activities of DNMTs are not required for LSH-mediated silencing. Our data suggest that LSH serves as a recruiting factor for DNMTs and HDACs to establish transcriptionally repressive chromatin which is perhaps further stabilized by DNA methylation at targeted loci.

* Corresponding author. Mailing address: Wellcome Trust Centre for Cell Biology, University of Edinburgh, Michael Swann Building, Mayfield Road, Edinburgh EH9 3JR, United Kingdom. Phone: 44 131 650 7029. Fax: 44 131 650 7063. E-mail: istancheva{at}ed.ac.uk

{triangledown} Published ahead of print on 29 October 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, January 2008, p. 215-226, Vol. 28, No. 1
0270-7306/08/$08.00+0     doi:10.1128/MCB.01073-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Branco, M. R., Oda, M., Reik, W. (2008). Safeguarding parental identity: Dnmt1 maintains imprints during epigenetic reprogramming in early embryogenesis. Genes Dev. 22: 1567-1571 [Abstract] [Full Text]  


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