Stulemeijer Iris J E, De Vos Dirk, van Harten Kirsten, Joshi Onkar K, Blomberg Olga, van Welsem Tibor, Terweij Marit, Vlaming Hanneke, de Graaf Erik L, Altelaar A F Maarten, Bakker Barbara M, van Leeuwen Fred
Division of Gene Regulation, Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands.
Department of Biology, University of Antwerp, Antwerp, 2020, Belgium.
Sci Rep. 2015 May 12;5:9824. doi: 10.1038/srep09824.
The conserved histone methyltransferase Dot1 establishes an H3K79 methylation pattern consisting of mono-, di- and trimethylation states on histone H3 via a distributive mechanism. This mechanism has been shown to be important for the regulation of the different H3K79 methylation states in yeast. Dot1 enzymes in yeast, Trypanosoma brucei (TbDot1A and TbDot1B, which methylate H3K76) and human (hDot1L) generate very divergent methylation patterns. To understand how these species-specific methylation patterns are generated, the methylation output of the Dot1 enzymes was compared by expressing them in yeast at various expression levels. Computational simulations based on these data showed that the Dot1 enzymes have highly distinct catalytic properties, but share a distributive mechanism. The mechanism of methylation and the distinct rate constants have implications for the regulation of H3K79/K76 methylation. A mathematical model of H3K76 methylation during the trypanosome cell cycle suggests that temporally-regulated consecutive action of TbDot1A and TbDot1B is required for the observed regulation of H3K76 methylation states.
保守的组蛋白甲基转移酶Dot1通过一种分布机制在组蛋白H3上建立了由单甲基化、二甲基化和三甲基化状态组成的H3K79甲基化模式。该机制已被证明对酵母中不同H3K79甲基化状态的调控很重要。酵母、布氏锥虫（TbDot1A和TbDot1B，它们使H3K76甲基化）和人类（hDot1L）中的Dot1酶产生非常不同的甲基化模式。为了了解这些物种特异性甲基化模式是如何产生的，通过在酵母中以各种表达水平表达Dot1酶来比较它们的甲基化输出。基于这些数据的计算模拟表明，Dot1酶具有高度不同的催化特性，但共享一种分布机制。甲基化机制和不同的速率常数对H3K79/K76甲基化的调控有影响。锥虫细胞周期中H3K76甲基化的数学模型表明，观察到的H3K76甲基化状态的调控需要TbDot1A和TbDot1B的时间调控连续作用。
