Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA.
Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA.
Cell. 2020 Jan 23;180(2):263-277.e20. doi: 10.1016/j.cell.2019.12.012. Epub 2020 Jan 16.
Cytosine methylation of DNA is a widespread modification of DNA that plays numerous critical roles. In the yeast Cryptococcus neoformans, CG methylation occurs in transposon-rich repeats and requires the DNA methyltransferase Dnmt5. We show that Dnmt5 displays exquisite maintenance-type specificity in vitro and in vivo and utilizes similar in vivo cofactors as the metazoan maintenance methylase Dnmt1. Remarkably, phylogenetic and functional analysis revealed that the ancestral species lost the gene for a de novo methylase, DnmtX, between 50-150 mya. We examined how methylation has persisted since the ancient loss of DnmtX. Experimental and comparative studies reveal efficient replication of methylation patterns in C. neoformans, rare stochastic methylation loss and gain events, and the action of natural selection. We propose that an epigenome has been propagated for >50 million years through a process analogous to Darwinian evolution of the genome.
DNA 的胞嘧啶甲基化是一种广泛存在的 DNA 修饰，在许多关键过程中发挥作用。在酵母新型隐球菌中，CG 甲基化发生在转座子丰富的重复序列中，需要 DNA 甲基转移酶 Dnmt5。我们表明，Dnmt5 在体外和体内表现出极高的维持型特异性，并利用类似于后生动物维持甲基转移酶 Dnmt1 的体内共因子。值得注意的是，系统发育和功能分析表明，在 50-150 百万年前，祖先物种失去了从头甲基转移酶 DnmtX 的基因。我们研究了自从古老的 DnmtX 缺失以来，甲基化是如何持续存在的。实验和比较研究揭示了新型隐球菌中甲基化模式的有效复制、罕见的随机甲基化丢失和获得事件，以及自然选择的作用。我们提出，一个表观基因组已经通过类似于基因组的达尔文进化过程传播了超过 5000 万年。
