Functional annotation of the human brain methylome identifies tissue-specific epigenetic variation across brain and blood

TLDR

Dynamic changes to the epigenome are critical for cellular phenotype, yet normal methylomic differences between distinct brain regions remain poorly understood. The study aimed to characterize intra‑ and inter‑individual methylomic variation across whole blood and multiple brain regions from multiple donors. The authors profiled DNA methylation across these tissues to assess variation patterns. Distinct tissue‑specific DNA methylation patterns were identified, with highly significant enrichment of TS‑DMRs at intragenic CpG islands and low‑CG promoters, many located near genes differentially expressed across brain regions and enriched in neurodevelopmental pathways, and while between‑tissue variation exceeded within‑tissue inter‑individual differences, some inter‑individual variation was shared between brain and blood, suggesting peripheral tissues may aid epidemiological studies of neurobiological phenotypes.

Abstract

Abstract Background 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. Results Distinct 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. Conclusions This 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.