Giaever Guri, Lissina Elena, Nislow Corey
Department of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada V6T 1Z3.
Microb Cell. 2019 Jul 9;6(8):356-369. doi: 10.15698/mic2019.08.687.
Sulfur assimilation and the biosynthesis of methionine, cysteine and S-adenosylmethionine (SAM) are critical to life. As a cofactor, SAM is required for the activity of most methyltransferases (MTases) and as such has broad impact on diverse cellular processes. Assigning function to MTases remains a challenge however, as many MTases are partially redundant, they often have multiple cellular roles and these activities can be condition-dependent. To address these challenges, we performed a systematic synthetic genetic analysis of all pairwise MTase double mutations in normal and stress conditions (16°C, 37°C, and LiCl) resulting in an unbiased comprehensive overview of the complexity and plasticity of the methyltransferome. Based on this network, we performed biochemical analysis of members of the histone H3K4 COMPASS complex and the phospholipid methyltransferase OPI3 to reveal a new role for a phospholipid methyltransferase in mediating histone methylation (H3K4) which underscores a potential link between lipid homeostasis and histone methylation. Our findings provide a valuable resource to study methyltransferase function, the dynamics of the methyltransferome, genetic crosstalk between biological processes and the dynamics of the methyltransferome in response to cellular stress.
硫同化以及甲硫氨酸、半胱氨酸和S-腺苷甲硫氨酸（SAM）的生物合成对生命至关重要。作为一种辅助因子，大多数甲基转移酶（MTases）的活性都需要SAM，因此它对多种细胞过程具有广泛影响。然而，确定MTases的功能仍然是一项挑战，因为许多MTases存在部分冗余，它们通常具有多种细胞作用，而且这些活性可能取决于条件。为应对这些挑战，我们在正常和应激条件（16°C、37°C和LiCl）下对所有成对的MTase双突变进行了系统的合成遗传分析，从而对甲基转移酶组的复杂性和可塑性有了无偏差的全面了解。基于此网络，我们对组蛋白H3K4 COMPASS复合物成员和磷脂甲基转移酶OPI3进行了生化分析，以揭示磷脂甲基转移酶在介导组蛋白甲基化（H3K4）中的新作用，这突出了脂质稳态与组蛋白甲基化之间的潜在联系。我们的研究结果为研究甲基转移酶功能、甲基转移酶组的动态变化、生物过程之间的遗传相互作用以及甲基转移酶组对细胞应激的反应提供了宝贵资源。
