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H3K27me3 shapes DNA methylome by inhibiting UHRF1-mediated H3 ubiquitination

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Abstract

DNA methylation and histone lysine tri-methylation at H3K27 (H3K27me3) are two chromatin modifications for transcriptional gene silencing, which play important roles in diverse biological processes, including cell fate determination and cell lineage commitment. These two marks are largely mutually exclusive and target distinct sets of genes in the mammalian genome. However, how H3K27me3 shapes the DNA methylome remains elusive. Here, we report that the loss of H3K27me3 modification leads to increased DNA methylation at previously marked H3K27me3 sites, indicating that H3K27me3 negatively regulates DNA methylation. Genome-wide analysis of H3 ubiquitination, essential for recruitment and activation of DNA methyltransferase DNMT1, reveals the absence of H3 ubiquitination at H3K27me3 marked nucleosomes. Moreover, loss of H3K27me3 modification induces an increase in H3K18 ubiquitination at the corresponding hyper-methylated loci. Importantly, we show that H3K27me3 directly inhibits UHRF1-mediated H3 ubiquitination toward nucleosomes in a defined biochemical assay. Taken together, our findings reveal a general mechanism for H3K27me3-mediated shaping of the mammalian DNA methylome via modulation of H3 ubiquitination.

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Data Availability

All WGBS, ChIP-seq, and RNA-seq datasets are deposited in the NCBI Gene Expression Omnibus (GEO) database under accession code GSE159043.

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Acknowledgements

This work was supported by the National Key Research and Development Program of China (2018YFA0107001, 2018YFC1004000), the CAS Project for Young Scientists in Basic Research (YSBR-012), and the National Natural Science Foundation of China (32070607). We thank Dr. Jiemin Wong from East China Normal University for the UHRF1 expression plasmid.

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  1. Contributed equally to this work

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  1. State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Innovative Academy of Seed Design, Chinese Academy of Sciences, Beijing, 100101, China

    Honglian Zhang, Ying Liu, Yali Xie, Yunji Zhu, Jingwen Liu & Falong Lu

  2. University of Chinese Academy of Sciences, Beijing, 100049, China

    Ying Liu, Yali Xie, Yunji Zhu, Jingwen Liu & Falong Lu

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  1. Honglian Zhang
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  2. Ying Liu
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  3. Yali Xie
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  4. Yunji Zhu
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  5. Jingwen Liu
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  6. Falong Lu
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Correspondence to Falong Lu.

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Zhang, H., Liu, Y., Xie, Y. et al. H3K27me3 shapes DNA methylome by inhibiting UHRF1-mediated H3 ubiquitination. Sci. China Life Sci. 65, 1685–1700 (2022). https://doi.org/10.1007/s11427-022-2155-0

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  • DOI: https://doi.org/10.1007/s11427-022-2155-0

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