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Title: CpG methylation differences between neurons and glia are highly conserved from mouse to human

item KESSLER, NOAH - Children'S Nutrition Research Center (CNRC)
item VAN BAAK, TIMOTHY - Children'S Nutrition Research Center (CNRC)
item BAKER, MARIA - Children'S Nutrition Research Center (CNRC)
item LARITSKY, ELEONORA - Children'S Nutrition Research Center (CNRC)
item COARFA, CRISTIAN - Baylor College Of Medicine
item WATERLAND, ROBERT - Children'S Nutrition Research Center (CNRC)

Submitted to: Human Molecular Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/5/2015
Publication Date: 1/15/2016
Citation: Kessler, N.J., Van Baak, T.E., Baker, M.S., Laritsky, E., Coarfa, C., Waterland, R.A. 2016. CpG methylation differences between neurons and glia are highly conserved from mouse to human. Human Molecular Genetics. 25(2):223-232.

Interpretive Summary: When most people think of brain cells, they think of neurons. However, in addition to neurons, the brain contains another major cell type: glia. In fact, there are approximately as many glia in the brain as there are neurons. Understanding the differential functions and maintenance of these two major cell types in the brain involves the science of epigenetics, which focuses on understanding the fundamental molecular mechanisms that stably regulate different patterns of gene expression in different cell types. A key epigenetic mark is DNA methylation, which occurs at so-called 'CpG sites' (a C followed by a G in the DNA sequence) in the genome. We re-analyzed a previously published data set on genome-wide CpG methylation in neurons and glia in brains of both mice and humans and made the novel discovery that across all genes, cell type-specific differences in this epigenetic mark are nearly 90% identical between mouse and human. This is important because it indicates that the mouse is an excellent animal model by which to understand epigenetic processes in the brain, meaning studies in mice will provide meaningful insights into human neuroepigenetic development and disease.

Technical Abstract: Understanding epigenetic differences that distinguish neurons and glia is of fundamental importance to the nascent field of neuroepigenetics. A recent study used genome-wide bisulfite sequencing to survey differences in DNA methylation between these two cell types, in both humans and mice. That study minimized the importance of cell type-specific differences in CpG methylation, claiming these are restricted to localized genomic regions, and instead emphasized that widespread and highly conserved differences in non-CpG methylation distinguish neurons and glia. We reanalyzed the data from that study and came to markedly different conclusions. In particular, we found widespread cell type-specific differences in CpG methylation, with a genome-wide tendency for neuronal CpG-hypermethylation punctuated by regions of glia-specific hypermethylation. Alarmingly, our analysis indicated that the majority of genes identified by the primary study as exhibiting cell type-specific CpG methylation differences were misclassified. To verify the accuracy of our analysis, we isolated neuronal and glial DNA from mouse cortex and performed quantitative bisulfite pyrosequencing at nine loci. The pyrosequencing results corroborated our analysis, without exception. Most interestingly, we found that gene-associated neuron vs. glia CpG methylation differences are highly conserved across human and mouse, and are very likely to be functional. In addition to underscoring the importance of independent verification to confirm the conclusions of genome-wide epigenetic analyses, our data indicate that CpG methylation plays a major role in neuroepigenetics, and that the mouse is likely an excellent model in which to study the role of DNA methylation in human neurodevelopment and disease.