LSH Cooperates with DNA Methyltransferases To Repress Transcription

Kevin Myant, Irina Stancheva

Research output: Contribution to journalArticlepeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)215-226
Number of pages12
JournalMolecular and Cellular Biology
Volume28
Issue number1
DOIs
Publication statusPublished - Jan 2008

Keywords

  • Cell Line
  • Cell Nucleus
  • DNA (Cytosine-5-)-Methyltransferase
  • DNA Helicases
  • DNA Modification Methylases
  • Histone Deacetylases
  • Humans
  • Protein Binding
  • Repressor Proteins
  • Transcription, Genetic

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