title: Suv39h-mediated histone H3 lysine 9 methylation directs DNA methylation to major satellite repeats at pericentric heterochromatin.
abstract: BACKGROUND
  Histone H3 lysine 9 (H3-K9) methylation and DNA methylation are characteristic hallmarks of mammalian heterochromatin. H3-K9 methylation was recently shown to be a prerequisite for DNA methylation in Neurospora crassa and Arabidopsis thaliana. Currently, it is unknown whether a similar dependence exists in mammalian organisms.
  
  
  RESULTS
  Here, we demonstrate a physical and functional link between the Suv39h-HP1 histone methylation system and DNA methyltransferase 3b (Dnmt3b) in mammals. Whereas in wild-type cells Dnmt3b interacts with HP1 alpha and is concentrated at heterochromatic foci, it fails to localize to these regions in Suv39h double null (dn) mouse embryonic stem (ES) cells. Consistently, the Suv39h dn ES cells display an altered DNA methylation profile at pericentric satellite repeats, but not at other repeat sequences. In contrast, H3-K9 trimethylation at pericentric heterochromatin is not impaired in Dnmt1 single- or Dnmt3a/Dnmt3b double-deficient ES cells. We also show that pericentric heterochromatin is not transcriptionally inert and can give rise to transcripts spanning the major satellite repeats.
  
  
  CONCLUSIONS
  These data demonstrate an evolutionarily conserved pathway between histone H3-K9 methylation and DNA methylation in mammals. While the Suv39h HMTases are required to direct H3-K9 trimethylation and Dnmt3b-dependent DNA methylation at pericentric repeats, DNA methylation at centromeric repeats occurs independent of Suv39h function. Thus, our data also indicate a more complex interrelatedness between histone and DNA methylation systems in mammals. Both methylation systems are likely to be important in reinforcing the stability of heterochromatic subdomains and thereby in protecting genome integrity.
authors.affiliation: Research Institute of Molecular Pathology (IMP), The Vienna Biocenter, Dr. Bohrgasse 7, A-1030 Vienna, Austria.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Lehnertz
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Ueda
authors.forename: Alwin A H A
authors.initials: AA
authors.lastname: Derijck
authors.forename: Ulrich
authors.initials: U
authors.lastname: Braunschweig
authors.forename: Laura
authors.initials: L
authors.lastname: Perez-Burgos
authors.forename: Stefan
authors.initials: S
authors.lastname: Kubicek
authors.forename: Taiping
authors.initials: T
authors.lastname: Chen
authors.forename: En
authors.initials: E
authors.lastname: Li
authors.forename: Thomas
authors.initials: T
authors.lastname: Jenuwein
authors.forename: Antoine H F M
authors.initials: AH
authors.lastname: Peters
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002874:Chromosome Mapping; D019175:DNA Methylation; D005455:Fluorescent Antibody Technique; D006570:Heterochromatin / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008745:Methylation; D008780:Methyltransferases / Q000378:metabolism*; D051379:Mice; D012097:Repressor Proteins / Q000378:metabolism*; D013234:Stem Cells; D020080:Tandem Repeat Sequences / Q000502:physiology; D014158:Transcription, Genetic
chemical_list: D006570:Heterochromatin; D006657:Histones; D012097:Repressor Proteins; C407843:SUV39H1 protein, human; C498700:Suv39h1 protein, mouse; D008780:Methyltransferases