The emergence of the brain non-CpG methylation system in vertebrates

Alex de Mendoza, Daniel Poppe, Sam Buckberry, Jahnvi Pflueger, Caroline B Albertin, Tasman Daish, Stephanie Bertrand, Elisa de la Calle-Mustienes, José Luis Gómez-Skarmeta, Joseph R Nery, Joseph R Ecker, Boris Baer, Clifton W Ragsdale, Frank Grützner, Hector Escriva, Byrappa Venkatesh, Ozren Bogdanovic, Ryan Lister

Research output: Contribution to journalArticlepeer-review

49 Citations (Scopus)
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Mammalian brains feature exceptionally high levels of non-CpG DNA methylation alongside the canonical form of CpG methylation. Non-CpG methylation plays a critical regulatory role in cognitive function, which is mediated by the binding of MeCP2, the transcriptional regulator that when mutated causes Rett syndrome. However, it is unclear whether the non-CpG neural methylation system is restricted to mammalian species with complex cognitive abilities or has deeper evolutionary origins. To test this, we investigated brain DNA methylation across 12 distantly related animal lineages, revealing that non-CpG methylation is restricted to vertebrates. We discovered that in vertebrates, non-CpG methylation is enriched within a highly conserved set of developmental genes transcriptionally repressed in adult brains, indicating that it demarcates a deeply conserved regulatory program. We also found that the writer of non-CpG methylation, DNMT3A, and the reader, MeCP2, originated at the onset of vertebrates as a result of the ancestral vertebrate whole-genome duplication. Together, we demonstrate how this novel layer of epigenetic information assembled at the root of vertebrates and gained new regulatory roles independent of the ancestral form of the canonical CpG methylation. This suggests that the emergence of non-CpG methylation may have fostered the evolution of sophisticated cognitive abilities found in the vertebrate lineage.

Original languageEnglish
Pages (from-to)369-378
Number of pages10
JournalNature Ecology and Evolution
Issue number3
Early online date18 Jan 2021
Publication statusPublished - Mar 2021


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