Table_2_Networking and Specificity-Changing DNA Methyltransferases in Helicobacter pylori.XLSX

Epigenetic DNA base methylation plays important roles in gene expression regulation. We here describe a gene expression regulation network consisting of many DNA methyltransferases each frequently changing its target sequence-specificity. Our object Helicobacter pylori, a bacterium responsible for most incidence of stomach cancer, carries a large and variable repertoire of sequence-specific DNA methyltransferases. By creating a dozen of single-gene knockout strains for the methyltransferases, we revealed that they form a network controlling methylome, transcriptome and adaptive phenotype sets. The methyltransferases interact with each other in a hierarchical way, sometimes regulated positively by one methyltransferase but negatively with another. Motility, oxidative stress tolerance and DNA damage repair are likewise regulated by multiple methyltransferases. Their regulation sometimes involves translation start and stop codons suggesting coupling of methylation, transcription and translation. The methyltransferases frequently change their sequence-specificity through gene conversion of their target recognition domain and switch their target sets to remodel the network. The emerging picture of a metamorphosing gene regulation network, or firework, consisting of epigenetic systems ever-changing their specificity in search for adaptation, provides a new paradigm in understanding global gene regulation and adaptive evolution.

表观遗传DNA碱基甲基化（Epigenetic DNA base methylation）在基因表达调控中发挥关键作用。本研究报道了一个由众多DNA甲基转移酶（DNA methyltransferases）构成的基因表达调控网络，其中每一类酶均可频繁改变其靶序列特异性。本研究的对象为幽门螺杆菌（Helicobacter pylori）——一种与绝大多数胃癌发病病例相关的致病菌——其基因组中编码了大量且具有序列特异性的可变DNA甲基转移酶库。我们通过构建十余株甲基转移酶单基因敲除菌株，发现这些酶共同构成了调控甲基组（methylome）、转录组（transcriptome）与适应性表型集合的调控网络。这些甲基转移酶以层级化方式相互调控：部分酶可被某一甲基转移酶正向激活，却又会对另一类酶产生负向抑制作用。细菌的运动能力、氧化应激耐受性以及DNA损伤修复通路同样受到多种甲基转移酶的调控。这类调控有时会涉及翻译起始密码子与终止密码子，这提示甲基化修饰、转录过程与翻译过程之间存在紧密的耦合关联。这些甲基转移酶可通过其靶识别结构域（target recognition domain）的基因转换事件，频繁改变自身的序列特异性，并通过切换靶位点集合来重塑整个调控网络。这一由表观遗传系统构成、可通过持续变更特异性以适应环境的动态蜕变型基因调控网络（或称“烟花网络”），为理解全局基因调控与适应性进化提供了全新的研究范式。