Université Paris Cité, CNRS, Epigenetics and Cell Fate, Paris, France.
Department of Biochemistry, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
Nat Commun. 2024 Apr 5;15(1):2960. doi: 10.1038/s41467-024-47314-4.
DNA methylation is an essential epigenetic chromatin modification, and its maintenance in mammals requires the protein UHRF1. It is yet unclear if UHRF1 functions solely by stimulating DNA methylation maintenance by DNMT1, or if it has important additional functions. Using degron alleles, we show that UHRF1 depletion causes a much greater loss of DNA methylation than DNMT1 depletion. This is not caused by passive demethylation as UHRF1-depleted cells proliferate more slowly than DNMT1-depleted cells. Instead, bioinformatics, proteomics and genetics experiments establish that UHRF1, besides activating DNMT1, interacts with DNMT3A and DNMT3B and promotes their activity. In addition, we show that UHRF1 antagonizes active DNA demethylation by TET2. Therefore, UHRF1 has non-canonical roles that contribute importantly to DNA methylation homeostasis; these findings have practical implications for epigenetics in health and disease.
DNA 甲基化是一种重要的表观遗传染色质修饰，其在哺乳动物中的维持需要 UHRF1 蛋白。目前尚不清楚 UHRF1 是否仅通过刺激 DNMT1 维持 DNA 甲基化来发挥作用，还是具有重要的其他功能。使用 degron 等位基因，我们表明 UHRF1 耗竭导致的 DNA 甲基化丧失比 DNMT1 耗竭更为严重。这不是由被动去甲基化引起的，因为 UHRF1 耗竭的细胞比 DNMT1 耗竭的细胞增殖更慢。相反，生物信息学、蛋白质组学和遗传学实验确立了 UHRF1 除了激活 DNMT1 之外，还与 DNMT3A 和 DNMT3B 相互作用并促进其活性。此外，我们表明 UHRF1 拮抗 TET2 的活性 DNA 去甲基化。因此，UHRF1 具有非典型的作用，对 DNA 甲基化的动态平衡有重要贡献；这些发现对健康和疾病中的表观遗传学具有实际意义。
