Evolutionary Persistence of DNA Methylation for Millions of Years after Ancient Loss of a De Novo Methyltransferase

• Published in: Cell Vol. 180; no. 2; pp. 263 - 277.e20
• Main Authors: Catania, Sandra, Dumesic, Phillip A., Pimentel, Harold, Nasif, Ammar, Stoddard, Caitlin I., Burke, Jordan E., Diedrich, Jolene K., Cooke, Sophie, Shea, Terrance, Gienger, Elizabeth, Lintner, Robert, Yates, John R., Hajkova, Petra, Narlikar, Geeta J., Cuomo, Christina A., Pritchard, Jonathan K., Madhani, Hiten D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23-01-2020
• Subjects: Biological Evolution; chromatin; Cryptococcus neoformans - genetics; Cryptococcus neoformans - metabolism; Cryptocococcus neoformans; DNA (Cytosine-5-)-Methyltransferase 1 - genetics; DNA (Cytosine-5-)-Methyltransferases - genetics; DNA - metabolism; DNA methylation; DNA Methylation - genetics; DNA Methylation - physiology; DNA Modification Methylases - genetics; DNA Transposable Elements - genetics; epigenetic memory; epigenetics; Epigenomics - methods; evolution; Evolution, Molecular; Genome - genetics; Methyltransferases - genetics; Methyltransferases - metabolism; Phylogeny; transposable elements; DNA methylation; evolution; chromatin; transposable elements; Cryptocococcus neoformans; epigenetics; epigenetic memory
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2019.12.012

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.
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•Exquisitely specific maintenance methylase enzyme drives all 5mC in C. neoformans•Once lost, methylation is not efficiently restored mitotically or meiotically•The de novo enzyme DnmtX was lost in an ancestral species ∼50–150 mya•Persistence of 5mC for millions of years explained by Darwinian epigenome evolution
The pathogenic fungus Cryptococcus neoformans encodes a functional maintenance methyltransferase for 5mC but no de novo enzyme; 5mC has been maintained for millions of years by a combintation of random epimutation and natural selection.