Liu Yanqing, Hrit Joel A, Chomiak Alison A, Stransky Stephanie, Hoffman Jordan R, Tiedemann Rochelle L, Wiseman Ashley K, Kariapper Leena S, Dickson Bradley M, Worden Evan J, Fry Christopher J, Sidoli Simone, Rothbart Scott B
Department of Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA.
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Mol Cell. 2025 Jan 16;85(2):394-412.e12. doi: 10.1016/j.molcel.2024.11.009. Epub 2024 Dec 3.
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.
由UHRF1催化的组蛋白H3赖氨酸18位点的单泛素化（H3K18ub）是一个DNMT1对接位点，有助于复制偶联的DNA甲基化维持。除此之外，其功能尚不清楚。在这里，我们通过基因组图谱描绘了在抑制DNMT1后，UHRF1依赖的H3K18ub和SUV39H1/H2依赖的H3K9me3同时增加的情况。从机制上讲，半甲基化DNA在CpG岛的短暂积累促进了UHRF1的募集以及其对H3K18的E3连接酶活性。值得注意的是，H3K18ub增强了SUV39H1/H2甲基转移酶的活性，并且在结肠癌细胞中，在DNA甲基化沉默的肿瘤抑制基因（TSG）的CpG岛启动子处形成新的H3K9me3结构域。破坏UHRF1酶活性可防止H3K9me3积累，同时促进PRC2依赖的H3K27me3作为这些区域基因抑制的第三层。相比之下，破坏H3K18ub依赖的SUV39H1/H2活性可增强DNMT1抑制的转录激活和抗增殖作用。总的来说，这些发现揭示了UHRF1和H3K18ub在调节抑制性组蛋白甲基化信号层次中的作用，并为表观遗传癌症治疗的联合策略提供了理论依据。
