Abstract
BackgroundDynamic changes to the epigenome play a critical role in establishing and maintaining cellular phenotype during differentiation, but little is known about the normal methylomic differences that occur between functionally distinct areas of the brain. We characterized intra- and inter-individual methylomic variation across whole blood and multiple regions of the brain from multiple donors.ResultsDistinct tissue-specific patterns of DNA methylation were identified, with a highly significant over-representation of tissue-specific differentially methylated regions (TS-DMRs) observed at intragenic CpG islands and low CG density promoters. A large proportion of TS-DMRs were located near genes that are differentially expressed across brain regions. TS-DMRs were significantly enriched near genes involved in functional pathways related to neurodevelopment and neuronal differentiation, including BDNF, BMP4, CACNA1A, CACA1AF, EOMES, NGFR, NUMBL, PCDH9, SLIT1, SLITRK1 and SHANK3. Although between-tissue variation in DNA methylation was found to greatly exceed between-individual differences within any one tissue, we found that some inter-individual variation was reflected across brain and blood, indicating that peripheral tissues may have some utility in epidemiological studies of complex neurobiological phenotypes.ConclusionsThis study reinforces the importance of DNA methylation in regulating cellular phenotype across tissues, and highlights genomic patterns of epigenetic variation across functionally distinct regions of the brain, providing a resource for the epigenetics and neuroscience research communities.
Highlights
Dynamic changes to the epigenome play a critical role in establishing and maintaining cellular phenotype during differentiation, but little is known about the normal methylomic differences that occur between functionally distinct areas of the brain
We observe that TS-differentially methylated region (DMR) are strikingly under-represented in classic promoter CpG island (CGI), being located primarily in intragenic CGIs and low CG content promoter (LCP)
These tissue-specific differentially methylated region (TS-DMR) are dramatically enriched for genes known to be involved in brain development and neurobiological function, forming networks of co-methylated loci that define the cellular phenotype
Summary
Dynamic changes to the epigenome play a critical role in establishing and maintaining cellular phenotype during differentiation, but little is known about the normal methylomic differences that occur between functionally distinct areas of the brain. We characterized intra- and inter-individual methylomic variation across whole blood and multiple regions of the brain from multiple donors. DNA methylation is a key epigenetic mechanism involved in the developmental regulation of gene expression [1], but the tissue-specific nature of DNA methylation has not been fully characterized at a genomic level. The importance of DNA methylation in normal brain function and development is exemplified by the neurodevelopmental deficits methylated DNA immunoprecipitation combined with ultra-deep sequencing (MeDIP-seq) to profile the methylomic landscape across multiple dissected brain regions and blood obtained from multiple individuals. We present annotated maps of the brain methylome, representing a unique resource for the genomics and neuroscience research communities, identifying key regions of the genome characterized by functionally relevant tissue-specific DNA methylation
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