Summary: Microglia exhibit DNA methylation patterns that are distinct from other central nervous system cells, and individual variability strongly influences their methylome.
Source: Elsevier
Microglial cells in the human brain are central to development, aging, homeostasis, and disease. While previous research has documented region-, age-, and disease-associated differences in microglial gene expression and phenotype, the underlying molecular mechanisms remain incompletely defined. A new study published in Biological Psychiatry focuses on DNA methylation—the principal epigenetic mechanism—to map the methylome of human microglia and identify factors that shape its variability.
The research characterizes genome-scale DNA methylation profiles of isolated primary microglia from post-mortem human brains to better understand how age, brain region, disease status, and individual-specific factors contribute to epigenetic variation in these brain-resident immune cells.
Microglia were historically viewed as a homogeneous cell population that alternated between inactive and activated states. Current evidence, however, shows that microglia adopt diverse phenotypes depending on their local environment, developmental stage, and pathological context. These phenotypes have important implications for neurological and psychiatric conditions, making it essential to decipher molecular regulators such as DNA methylation that can influence microglial gene expression and function.
Senior author Fatemeh Haghighi, Ph.D., explains that the study set out to “characterize the DNA methylation landscape of human primary microglia and factors that contribute to variations in the microglia methylome.” The authors applied genome-wide methylation arrays to microglia isolated from multiple brain regions and donors to reveal the epigenetic architecture of these cells in health and disease.
DNA methylation is a dominant form of epigenetic regulation that helps determine whether genes are expressed or silenced over time and in response to changing conditions. Mapping methylation in microglia clarifies how epigenetic modification may contribute to functional states and disease-related changes.
The study analyzed microglia isolated from post-mortem tissue obtained from 22 donors of varying ages. The cohort included one individual with schizophrenia, 13 with mood disorder pathology, and eight controls without psychiatric diagnoses. Samples were taken from four different brain regions and profiled using genome-scale methylation microarrays to capture methylation across the genome in purified microglia populations.
As expected, microglia exhibited methylation profiles that were clearly distinct from bulk brain tissue and from neuronal cells. Notably, the investigators found that interindividual differences—variability between people—had a larger effect on microglial DNA methylation than did differences between brain regions. Age also explained a substantial portion of methylation variation. In exploratory analyses, the team identified differentially methylated regions associated with mood disorder pathology versus controls, implicating loci tied to microglial gene expression, myeloid cell function, and neuropsychiatric disease mechanisms.
John Krystal, MD, Editor of Biological Psychiatry, noted that these data “point to pathology of the microglia, key immune cells of the brain, in the biology of depression,” highlighting the potential relevance of microglial epigenetic alterations to mood disorders.
About this genetics and neuroscience research news
Author: Press Office
Source: Elsevier
Contact: Press Office – Elsevier
Image: The image is in the public domain
Original Research: Open access.
Title: Contribution of age, brain region, mood disorder pathology, and interindividual factors on the methylome of human microglia — Lot D. de Witte et al., Biological Psychiatry
Abstract
Contribution of age, brain region, mood disorder pathology, and interindividual factors on the methylome of human microglia
Background
Transcriptome analyses have documented microglial phenotypes associated with age, disease, and brain region, reflecting dynamic changes in microglial function during development, aging, and disease. Despite these transcriptomic insights, the epigenetic mechanisms that drive or accompany these expression changes are not well characterized. The present study aimed to map the DNA methylation landscape of human microglia and evaluate how age, brain region, disease status, and individual-specific factors influence that landscape. The authors hypothesized that both age and brain region would substantially shape microglial methylation profiles.
Methods
Microglia were isolated from post-mortem tissue across four brain regions in 22 donors, including individuals diagnosed with schizophrenia (n=1), mood disorders (n=13), and non-psychiatric controls (n=8). Purified microglial DNA was assayed using a genome-wide methylation array to capture methylation variation at high resolution.
Results
Human microglia displayed methylation profiles that differed markedly from bulk brain tissue and from neuronal methylomes. Age accounted for a notable portion of methylation variance. Importantly, interindividual differences contributed more to methylation variability than did differences between brain regions, a pattern consistent with prior transcriptome observations. Exploratory analyses identified several differentially methylated regions associated with mood disorder status compared with controls; some of these regions correspond to genes with roles in microglial or myeloid function and have links to neuropsychiatric disorders.
Conclusions
Although based on a relatively small sample, the findings indicate that the microglial methylome is shaped by interindividual variation and age, and that this epigenetic heterogeneity likely contributes to the diversity of microglial transcriptomic states observed across people and conditions. These results support a role for microglial epigenetic regulation in brain health and disease and underscore the importance of considering individual-specific factors in studies of microglia and neuropsychiatric pathology.