DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA (original) (raw)

Nature volume 448, pages 714–717 (2007)Cite this article

Abstract

Mammals use DNA methylation for the heritable silencing of retrotransposons and imprinted genes and for the inactivation of the X chromosome in females. The establishment of patterns of DNA methylation during gametogenesis depends in part on DNMT3L, an enzymatically inactive regulatory factor that is related in sequence to the DNA methyltransferases DNMT3A and DNMT3B1,2. The main proteins that interact in vivo with the product of an epitope-tagged allele of the endogenous Dnmt3L gene were identified by mass spectrometry as DNMT3A2, DNMT3B and the four core histones. Peptide interaction assays showed that DNMT3L specifically interacts with the extreme amino terminus of histone H3; this interaction was strongly inhibited by methylation at lysine 4 of histone H3 but was insensitive to modifications at other positions. Crystallographic studies of human DNMT3L showed that the protein has a carboxy-terminal methyltransferase-like domain and an N-terminal cysteine-rich domain. Cocrystallization of DNMT3L with the tail of histone H3 revealed that the tail bound to the cysteine-rich domain of DNMT3L, and substitution of key residues in the binding site eliminated the H3 tail–DNMT3L interaction. These data indicate that DNMT3L recognizes histone H3 tails that are unmethylated at lysine 4 and induces de novo DNA methylation by recruitment or activation of DNMT3A2.

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Acknowledgements

We thank C.S. Lin for advice and assistance, D. Bourc’his, M. Damelin, C. Schaefer, X. Zhang and R. E. Collins for helpful discussions, J. R. Horton for collection of X-ray diffraction data, A. Ruthenberg for recombinant WDR5 protein, and K. Anderson, D. Bourc’his and C. Schaefer for criticism of the manuscript. This work was supported by grants from the National Institutes of Health to C. D. A., X. C., P. T. and T. H. B. and by a fellowship from the European Molecular Biology Organisation to S.K.T.O.

The X-ray structures of DNMT3L and the DNMT3L-H3 tail complex have been submitted to PDB as 2PV0 and 2PVC, respectively.

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Author notes

  1. Steen K. T. Ooi, Chen Qiu, Emily Bernstein and Keqin Li: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Genetics and Development, College of Physicians and Surgeons of Columbia University, New York, New York 10032, USA,
    Steen K. T. Ooi & Timothy H. Bestor
  2. Department of Biochemistry, Emory University, Atlanta, Georgia 30322, USA,
    Chen Qiu, Keqin Li, Da Jia, Zhe Yang & Xiaodong Cheng
  3. Laboratory of Chromatin Biology, The Rockefeller University, New York, New York 10021, USA,
    Emily Bernstein & C. David Allis
  4. Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA,
    Hediye Erdjument-Bromage & Paul Tempst
  5. Institute of Biotechnology, National Taiwan University, Taipei 106, Taiwan,
    Shau-Ping Lin

Authors

  1. Steen K. T. Ooi
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  2. Chen Qiu
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  3. Emily Bernstein
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  4. Keqin Li
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  5. Da Jia
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  6. Zhe Yang
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  7. Hediye Erdjument-Bromage
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  8. Paul Tempst
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  9. Shau-Ping Lin
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  10. C. David Allis
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  11. Xiaodong Cheng
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  12. Timothy H. Bestor
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Corresponding authors

Correspondence toXiaodong Cheng or Timothy H. Bestor.

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Ooi, S., Qiu, C., Bernstein, E. et al. DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA.Nature 448, 714–717 (2007). https://doi.org/10.1038/nature05987

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