TY - JOUR
T1 - Suv39h-mediated histone H3 lysine 9 methylation directs DNA methylation to major satellite repeats at pericentric heterochromatin
AU - Lehnertz, Bernhard
AU - Ueda, Yoshihide
AU - Derijck, Alwin A.H.A.
AU - Braunschweig, Ulrich
AU - Perez-Burgos, Laura
AU - Kubicek, Stefan
AU - Chen, Taiping
AU - Li, En
AU - Jenuwein, Thomas
AU - Peters, Antoine H.F.M.
N1 - Funding Information: We would like to thank Rudolf Jaenisch for providing α-Dnmt1 antibodies and Ted Rasmussen for sharing unpublished results. This work was supported by grants from the National Institutes of Health (CA82389 and GM52106) to E.L., the Japan Society for the Promotion of Science to Y.U., the Dutch Cancer Society-Koningin Wilhelmina Fonds (KWF) to A.A.H.A.D., and by a Marie Curie Industry Host Fellowship to A.H.F.M.P. Research in the laboratory of T.J. is supported by the Research Institute of Molecular Pathology through Boehringer Ingelheim, by grants from the Vienna Economy Promotion Fund (WWFF), by an EU-network grant (HPRN-CT 2000-00078), and by the Austrian GEN-AU initiative.
PY - 2003/7/15
Y1 - 2003/7/15
N2 - 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 HP1α 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.
AB - 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 HP1α 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.
UR - http://www.scopus.com/inward/record.url?scp=10744230544&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/S0960-9822(03)00432-9
DO - https://doi.org/10.1016/S0960-9822(03)00432-9
M3 - Article
C2 - 12867029
SN - 0960-9822
VL - 13
SP - 1192
EP - 1200
JO - Current biology
JF - Current biology
IS - 14
ER -