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

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.

Key words: :

• DNA methylation
• comparative epigenetics
• evolutionary conservation
• human brain
• mouse brain
• prefrontal cortex
• auditory cortex
• CpG island shore

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

We like to thank Dr. J. John Mann for his effort in conducting psychological autopsies of the human samples and his valuable comments in preparation of the manuscript. Also, Dr. John Smiley for his efforts in dissection of auditory cortex specimens.

Financial Support

This work was supported by grants from the National Institute of Mental Health (MH048514) and the National Human Genome Research institute (HG002915). A.H.O. was supported by an NRSA F30 fellowship from the NIMH (MH085471). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Note

Supplemental material can be found at: www.landesbioscience.com/journals/epigenetics/article/17876