Suv39h-mediated histone H3 lysine 9 methylation directs DNA methylation to major satellite repeats at pericentric heterochromatin.

By B. Lehnertz, Y. Ueda, A. Derijck, Ulrich Braunschweig, Laura Pérez-Burgos, S. Kubicek, Taiping Chen, E. Li, T. Jenuwein, A. Peters. Current Biology, 2003

1,302 citations recorded by the source corpus.

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.

Subfields: Molecular Biology, Plant Science

View Paper: https://www.semanticscholar.org/paper/cbcdf9c4105b9f432a2da4efb817e89a2cd40a08

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In Molecular Biology

1. Yi Zhang
2. Peter A. Jones
3. Manel Esteller
4. D. Reinberg
5. C. D. Allis
6. T. Jenuwein
7. M. Blasco
8. Cyrus Martin

In Plant Science

1. M. Blasco
2. Bing Ren
3. E. Li
4. Yi Zhang
5. M. Fraga
6. Peter A. Jones
7. R. Martienssen
8. Tom Misteli

Citations in the corpus

• How is pluripotency determined and maintained? (2007, background): “…machineries in pluripotent stem cells KO embryos KO ES cells Gene Phenotype ICM outgrowth Proliferation Marker expression Differentiation Restore by transgene Reference H3K9HMTases Suv39h1/h2 Viable NT Normal Normal Normal NT Peters et al., 2001; Lehnertz et al., 2003 G9a (Ehmt2) Die at E9.”
• DNA methylation: superior or subordinate in the epigenetic hierarchy? (2011, background): “and EZH2, respectively, interact directly with DNMT1, DNMT3A, and DNMT3B.(26,27) Pericentromeric localization of DNMT3B depends on SUV39H1/ 2-mediated H3K9 dimethylation or trimethylation.”
• Chromatin Structure and the Inheritance of Epigenetic Information (2010, background): “Knockdown of SUV39H1, SUV39H2 or G9A has an impact on DNA methylation at defined loc”
• Epigenetics in human disease and prospects for epigenetic therapy (2004, background): “, and this has also been shown in mammals, where H3-K9 methylation directs DNA methylation to pericentromeric heterochromati”
• Linking DNA methylation and histone modification: patterns and paradigms (2009, background): “These proteins are also required to recruit DNMT3A and DNMT3B in order to methylate CpG sites in the satellite sequence”
• Daxx is an H3.3-specific histone chaperone and cooperates with ATRX in replication-independent chromatin assembly at telomeres (2010, background): “3: abnormal telomeres, aberrant chromosome segregation and premature sister chromatid separation (41, 42).”
• The diverse functions of histone lysine methylation (2005, background): “Interestingly, genetic studies have shown in a number of organisms that H3-K9 methylation is a prerequisite for DNA methylation 128–130 .”
• DNA methylation: The nuts and bolts of repression (2007, background): “…Arabidopsis, mutations in the histone H3K9 methyltransferase caused significant loss of genomic DNA methylation and in mammalian cells SUV39 has been shown to be required for Dnmt3b-dependent DNA methylation at pericentric repeats (Jackson et al., 2002; Lehnertz et al., 2003; Tamaru et al., 2003).”
• ATM signaling facilitates repair of DNA double-strand breaks associated with heterochromatin. (2008, background): “Knockout of the Suv39H1 and Suv39H2 histone methyltransferases in MEFs leads to a reduction in histone H3 trimethylation, altered DNA methylation, and HP1 localization within pericentric heterochromatin (Lehnertz et al., 2003).”
• Histone H1 depletion in mammals alters global chromatin structure but causes specific changes in gene regulation. (2005, methodology): “Digestion with MspI or HpaII, followed by Southern blot hybridization with a probe specific for the mouse minor satellite repeat (Lehnertz et al., 2003), did not show a difference in these sequences that are present as 50,000–100,000 copies localized in centromeric regions (Kalitis and Choo, 1989) (”