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. 2025 Jan 16;85(2):394-412.e12.
doi: 10.1016/j.molcel.2024.11.009. Epub 2024 Dec 3.

DNA hypomethylation promotes UHRF1-and SUV39H1/H2-dependent crosstalk between H3K18ub and H3K9me3 to reinforce heterochromatin states

Yanqing Liu  1 , Joel A Hrit  1 , Alison A Chomiak  1 , Stephanie Stransky  2 , Jordan R Hoffman  3 , Rochelle L Tiedemann  1 , Ashley K Wiseman  1 , Leena S Kariapper  4 , Bradley M Dickson  1 , Evan J Worden  4 , Christopher J Fry  3 , Simone Sidoli  2 , Scott B Rothbart  5
Affiliations

DNA hypomethylation promotes UHRF1-and SUV39H1/H2-dependent crosstalk between H3K18ub and H3K9me3 to reinforce heterochromatin states

Yanqing Liu et al. Mol Cell. .

Abstract

Mono-ubiquitination of lysine 18 on histone H3 (H3K18ub), catalyzed by UHRF1, is a DNMT1 docking site that facilitates replication-coupled DNA methylation maintenance. Its functions beyond this are unknown. Here, we genomically map simultaneous increases in UHRF1-dependent H3K18ub and SUV39H1/H2-dependent H3K9me3 following DNMT1 inhibition. Mechanistically, transient accumulation of hemi-methylated DNA at CpG islands facilitates UHRF1 recruitment and E3 ligase activity toward H3K18. Notably, H3K18ub enhances SUV39H1/H2 methyltransferase activity and, in colon cancer cells, nucleates new H3K9me3 domains at CpG island promoters of DNA methylation-silenced tumor suppressor genes (TSGs). Disrupting UHRF1 enzyme activity prevents H3K9me3 accumulation while promoting PRC2-dependent H3K27me3 as a tertiary layer of gene repression in these regions. By contrast, disrupting H3K18ub-dependent SUV39H1/H2 activity enhances the transcriptional activating and antiproliferative effects of DNMT1 inhibition. Collectively, these findings reveal roles for UHRF1 and H3K18ub in regulating a hierarchy of repressive histone methylation signaling and rationalize a combination strategy for epigenetic cancer therapy.

Keywords: DNA methylation; SUV39H1/H2; UHRF1; epigenetic therapy; histone methylation; histone ubiquitination.

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Conflict of interest statement

Declaration of interests C.J.F. and J.R.H. are paid employees of Cell Signaling Technology.

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