Suv39h-mediated histone H3 lysine 9 methylation directs DNA methylation to major satellite repeats at pericentric heterochromatin.
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.
Lehnertz
Bernhard
B
Research Institute of Molecular Pathology (IMP), The Vienna Biocenter, Dr. Bohrgasse 7, A-1030 Vienna, Austria.
Ueda
Yoshihide
Y
Derijck
Alwin A H A
AA
Braunschweig
Ulrich
U
Perez-Burgos
Laura
L
Kubicek
Stefan
S
Chen
Taiping
T
Li
En
E
Jenuwein
Thomas
T
Peters
Antoine H F M
AH
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
D006570:Heterochromatin; D006657:Histones; D012097:Repressor Proteins; C407843:SUV39H1 protein, human; C498700:Suv39h1 protein, mouse; D008780:Methyltransferases