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

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...

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Detalhes bibliográficos
Autores: Mendoza, Alex de, Poppe, Daniel, Buckberry, Sam, Pfluege, Jahnvi, Albertin, Caroline B., Daish, Tasman, Bertrand, Stephanie, Calle-Mustienes, Elisa de la, Gómez-Skarmeta, José Luis, Nery, Joseph R., Ecker, Joseph R., Baer, Boris, Ragsdale, Clifton W., Grützner, Frank, Escrivá, Héctor, Venkatesh, Byrappa, Bogdanovic, Ozren, Lister, Ryan
Formato: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2021
País:España
Recursos:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/260305
Acesso em linha:http://hdl.handle.net/10261/260305
Access Level:acceso abierto
Palavra-chave:Comparative genomics
Epigenomics
Evolutionary developmental biology
Molecular evolution
Descrição
Resumo: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.

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