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EPIGENOMICS

DNMT3A binds ubiquitinated histones to regulate bivalent genes

Nature Genetics volume 54, pages 537–538 (2022)Cite this article

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A new study demonstrates that the disordered N-terminal domain of DNMT3A1 binds PRC1-catalyzed H2AK119ub, targeting DNA methylation to bivalent promoters in mouse brain cortical cells. Methylation around bivalent genes is critical for mouse postnatal development, and could be equally important in other cell types and in disease.

To investigate the difference between the two isoforms of Dnmt3a, the authors generated isoform-specific knockout mice and found that, although Dnmt3a2–/– mice had no altered phenotype, Dnmt3a1–/– mice were similar to Dnmt3a–/– knockouts2,8. Because they found that Dnmt3a1 is predominantly expressed in the brain, and indeed re-expression in the brain could partially rescue the knockout phenotype, they focused there for mechanistic experiments.

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Fig. 1: DNMT3A1 has a disordered N-terminal domain, missing from the other isoform DNMT3A2, that binds ubiquitinated lysine 119 on histone H2A (H2AK119ub).

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Authors and Affiliations

  1. Epigenetics Programme, The Babraham Institute, Cambridge, UK

    Aled J. Parry & Wolf Reik

  2. Altos Labs Cambridge Institute, Cambridge, UK

    Wolf Reik

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  1. Aled J. Parry
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  2. Wolf Reik
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Correspondence to Aled J. Parry.

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Competing interests

W.R. is a consultant and shareholder of Cambridge Epigenetix. W.R. is employed by Altos Labs. The remaining authors declare no competing interests.

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Parry, A.J., Reik, W. DNMT3A binds ubiquitinated histones to regulate bivalent genes. Nat Genet 54, 537–538 (2022). https://doi.org/10.1038/s41588-022-01073-4

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