Role of CpG context and content in evolutionary signatures of brain DNA methylation

Yurong Xin, Anne H. O'Donnell, Yongchao Ge, Benjamin Chanrion, Maria Milekic, Gorazd Rosoklija, Aleksandar Stankov, Victoria Arango, Andrew J. Dwork, Jay A. Gingrich, Fatemeh G. Haghighi

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

DNA methylation is essential in brain function and behavior; therefore, understanding the role of DNA methylation in brain-based disorders begins with the study of DNA methylation profiles in normal brain. Determining the patterns and scale of methylation conservation and alteration in an evolutionary context enables the design of focused but effective methylation studies of disease states. We applied an enzymatic-based approach, Methylation Mapping Analysis by Paired-end Sequencing (Methyl-MAPS), which utilizes second-generation sequencing technology to provide an unbiased representation of genome-wide DNA methylation profiles of human and mouse brains. In this large-scale study, we assayed CpG methylation in cerebral cortex of neurologically and psychiatrically normal human postmortem specimens, as well as mouse forebrain specimens. Cross-species human-mouse DNA methylation conservation analysis shows that DNA methylation is not correlated with sequence conservation. Instead, greater DNA methylation conservation is correlated with increasing CpG density. In addition to CpG density, these data show that genomic context is a critical factor in DNA methylation conservation and alteration signatures throughout mammalian brain evolution. We identify key genomic features that can be targeted for identification of epigenetic loci that may be developmentally and evolutionarily conserved and wherein aberrations in DNA methylation patterns can confer risk for disease.

Original languageEnglish
Pages (from-to)1308-1318
Number of pages11
JournalEpigenetics
Volume6
Issue number11
DOIs
StatePublished - Nov 2011

Keywords

  • Auditory cortex
  • Comparative epigenetics
  • CpG island shore
  • DNA methylation
  • Evolutionary conservation
  • Human brain
  • Mouse brain
  • Prefrontal cortex

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