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Abstract Background DNA methylation dynamics in the brain are associated with normal development and neuropsychiatric disease and differ across functionally distinct brain regions. Previous studies of genome-wide methylation differences among human brain regions focus on limited numbers of individuals and one to two brain regions. Results Using GTEx samples, we generate a resource of DNA methylation in purified neuronal nuclei from 8 brain regions as well as lung and thyroid tissues from 12 to 23 donors. We identify differentially methylated regions between brain regions among neuronal nuclei in both CpG (181,146) and non-CpG (264,868) contexts, few of which were unique to a single pairwise comparison. This significantly expands the knowledge of differential methylation across the brain by 10-fold. In addition, we present the first differential methylation analysis among neuronal nuclei from basal ganglia tissues and identify unique CpG differentially methylated regions, many associated with ion transport. We also identify 81,130 regions of variably CpG methylated regions, i.e., variable methylation among individuals in the same brain region, which are enriched in regulatory regions and in CpG differentially methylated regions. Many variably methylated regions are unique to a specific brain region, with only 202 common across all brain regions, as well as lung and thyroid. Variably methylated regions identified in the amygdala, anterior cingulate cortex, and hippocampus are enriched for heritability of schizophrenia. Conclusions These data suggest that epigenetic variation in these particular human brain regions could be associated with the risk for this neuropsychiatric disorder.
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A Tissue Comparison of DNA Methylation of the Glucocorticoid Receptor Gene (Nr3c1) in European Starlings
Abstract Negative feedback of the vertebrate stress response via the hypothalamic–pituitary–adrenal (HPA) axis is regulated by glucocorticoid receptors in the brain. Epigenetic modification of the glucocorticoid receptor gene (Nr3c1), including DNA methylation of the promoter region, can influence expression of these receptors, impacting behavior, physiology, and fitness. However, we still know little about the long-term effects of these modifications on fitness. To better understand these fitness effects, we must first develop a non-lethal method to assess DNA methylation in the brain that allows for multiple measurements throughout an organism’s lifetime. In this study, we aimed to determine if blood is a viable biomarker for Nr3c1 DNA methylation in two brain regions (hippocampus and hypothalamus) in adult European starlings (Sturnus vulgaris). We found that DNA methylation of CpG sites in the complete Nr3c1 putative promoter varied among tissue types and was lowest in blood. Although we identified a similar cluster of correlated Nr3c1 putative promoter CpG sites within each tissue, this cluster did not show any correlation in DNA methylation among tissues. Additional studies should consider the role of the developmental environment in producing epigenetic modifications in different tissues.
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- Award ID(s):
- 1840903
- PAR ID:
- 10129457
- Date Published:
- Journal Name:
- Integrative and Comparative Biology
- Volume:
- 59
- Issue:
- 2
- ISSN:
- 1540-7063
- Page Range / eLocation ID:
- 264 to 272
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1093/icb/icz034
