While conducting epigenomics research, we are often faced with a number of brain teasers. To solve these cognitive conundrums, many of us turn to diseases and disorders to learn about healthy conditions. However, the methylation maestros in the labs of Andrew Feinberg and Kasper Hansen at John Hopkins University (Maryland, USA) now demonstrate the utility of assaying different brain regions from healthy people to understand the riddle of psychiatric disorders.
The talented team examined four brain regions from the same six healthy people (three males and three females) aged between 37-57, which included the:
- Anterior cingulate gyrus (BA24), which regulates emotions and behavior
- Hippocampus (HC), which is involved in learning and memory
- Prefrontalcortex (BA9), which plays a role in cognition
- Nucleus accumbens (NAcc), which controls reward behavior and addiction
To interrogate the regional epigenomic differences, the authors utilized whole-genome bisulfite sequencing (WGBS) to examine DNA methylation from all four regions. For the prefrontal cortex and nucleus accumbens, they integrated methylome data with ATAC-seq and RNA-seq to examine chromatin accessibility and gene expression, respectively. This sequencing approach enabled the examination of sorted neuronal and non-neuronal (primarily glia) nuclei from the four regions mentioned above and focused on pronounced differences (>10%) in methylated CpG and non-CpG regions (CG-DMRs and CH-DMRs).
Here’s what they uncovered:
- The ~13,000 autosomal neuronal CG-DMRs between the brain regions cover 12 Mb of the genome and are:
- enriched for known gene regulatory regions and chromatin states
- consistent with chromatin accessibility
- typically found in introns
- obscured by cell type heterogeneity in bulk brain tissue, where there are only ~70 CG-DMRs between regions
- Glia populations display very few (~115) CG-DMRs between brain regions
- Neuronal CH-DMRs cover 40 Mb of the genome, and are highly enriched for CG-DMRs (~15% overlap), but show a stronger enrichment than CG-DMRs for differentially expressed genes and their promoters
- Neuronal CG-DMRs display enrichment for genome-wide association study (GWAS) hits related to the heritability of neuropsychiatric traits such as schizophrenia, addictive behavior, and neuroticism
Co-Senior author Andrew Feinberg shares, “We believe we have figured out what parts of the neuronal genome are epigenetically different among these four brain regions. And these areas are enriched with inherited genetic variants linked to certain psychiatric conditions. We do know that both epigenetic and genetic changes contribute to the problem of cells not doing what they’re supposed to do. To reveal how epigenetics is linked to psychiatric conditions, the next step is to develop customized genomic arrays that capture the areas of the genome that we identified and compare them to more samples of people with and without psychiatric disease.
Tease apart the brain’s regional epigenomic differences in Nature Neuroscience, January 2019