Not much is known about the normal DNA methylation differences between functionally different parts of the brain or how they relate to the patterns in peripheral tissues like blood. In a new study, scientists extensively mapped out the brain methylome to create a baseline resource for use in future research efforts.
Researchers from King’s College London profiled the methylomes of multiple dissected brain regions and blood from several individuals. “The key motivation for this study was that very little is known about “normal” patterns of epigenetic variation across different regions of the brain, and how intra-individual patterns of DNA methylation differ across brain and blood” commented Jonathan Mill who headed up the research group.
The U.K. based team used methylated DNA immunoprecipitation sequencing (MeDIP-seq) to interrogate brain segments including the inferior frontal gyrus, middle frontal gyrus, entorhinal cortex, superior temporal gyrus of the temporal cortex, visual cortex, and cerebellum from samples without any neuropathology or neuropsychiatric disease. “We hoped to identify regions of the methylome that define different types of tissue, and understand more about whether blood can be used as a proxy for brain in epidemiological studies aiming to identify disease biomarkers”, said Mill. After the smoke cleared, here are the highlights from their experiments:
- Genome-wide DNA methylation signatures were very specific across cortex, cerebellum and peripheral blood.
- DNA methylation varied among genomic regions, and tissues
- Tissue Specific Differentially Methylated Regions (TS-DMRs) between brain regions were tied to stable gene expression differences and involved in functionally relevant neurobiological pathways
- Even functionally different regions of the same tissue, the cerebral cortex, showed DNA methylation variation.
- Promoter CpG Island (CGI) stays steady throughout brain areas and blood, but intragenic CGIs show strong tissue-specific DNA methylation
- Generally, greater tissue-specific DNA methylation is seen at CGI shores than CGIs.
- Promoters with low CG content demonstrate widespread tissue-specific DNA methylation across brain regions as well as blood.
- There is some correlation between brain and blood in terms of individual differences in DNA methylation.
Not all of these results were entirely expected. “It was interesting that intra-individual inter-tissue variation in DNA methylation far exceeded inter-individual variation in any given tissue. DNA methylation across intragenic CpG islands and low CG content promoters was found to be particularly important in defining tissue-specific variation. We also observed that although brain tissue and blood have very distinct methylomic profiles, as would be expected, some inter-individual variation is correlated across tissues. It is plausible that some of this may result from genetic effects on DNA methylation, or the effects of environmental or stochastic events occurring early in development.” Commented Mill.
The King’s College crew anticipate that their data will become a valuable resource for further genomics efforts, and they’ve made the UCSC tracks available on the Mill lab website, and begun integrating the raw data into the Human Epigenome Atlas (part of the NIH Epigenomics Roadmap Initiative) for others to freely use.
Dr. Mill commented that, “Understanding these things is an important first step in our efforts to examine the role of epigenetic processes in disorders such as schizophrenia, autism and dementia.” Mill goes on to explain that “These results are important because regions defined as TS-DMRs are likely to be key regulators of cellular phenotype, and altered DNA methylation across these regions could play a key role in regulating health and disease. “
Give your mind a boost with all of the brain methylome details at Genome Biology, June 2012.