Contribution of Age, Brain Region, Mood Disorder Pathology, and Interindividual Factors on the Methylome of Human Microglia
de Witte, Lot D.; Wang, Zhaoyu; Snijders, Gijsje L.J.L.; Mendelev, Natalia; Liu, Qingkun; Sneeboer, Marjolein A.M.; Boks, Marco P.M.; Ge, Yongchao; Haghighi, Fatemeh
(2022) Biological Psychiatry, volume 91, issue 6, pp. 572 - 581
(Article)
Abstract
Background: Transcriptome studies have revealed age-, disease-, and region-associated microglial phenotypes reflecting changes in microglial function during development, aging, central nervous system homeostasis, and pathology. The molecular mechanisms that contribute to these transcriptomic changes are largely unknown. The aim of this study was to characterize the DNA methylation landscape of
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human microglia and the factors that contribute to variations in the microglia methylome. We hypothesized that both age and brain region would have a large impact on DNA methylation in microglia. Methods: Microglia from postmortem brain tissue of four different brain regions of 22 donors, encompassing 1 patient with schizophrenia, 13 patients with mood disorder pathology, and 8 control subjects, were isolated and assayed using a genome-wide methylation array. Results: We found that human microglial cells have a methylation profile distinct from bulk brain tissue and neurons, and age explained a considerable part of the variation. Additionally, we showed that interindividual factors had a much larger effect on the methylation landscape of microglia than brain region, which was also seen at the transcriptome level. In our exploratory analysis, we found various differentially methylated regions that were related to disease status (mood disorder vs. control). This included differentially methylated regions that are linked to gene expression in microglia, as well as to myeloid cell function or neuropsychiatric disorders. Conclusions: Although based on relatively small samples, these findings suggest that the methylation profile of microglia is responsive to interindividual variations and thereby plays an important role in the heterogeneity of microglia observed at the transcriptome level.
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Keywords: Bipolar disorder, Brain region, Depression, Methylation, Microglia, Transcriptome, DNA Methylation, Microglia/metabolism, Mood Disorders/genetics, Humans, Epigenome, Brain/metabolism, Biological Psychiatry, Research Support, U.S. Gov't, Non-P.H.S., Journal Article
ISSN: 0006-3223
Publisher: Elsevier USA
Note: Funding Information: This study was supported by the psychiatric donor program of the Netherlands Brain Bank , which is supported by the Netherlands Organization for Scientific Research; the Catharina van Tussenbroek Fund, the Jo Kolk Study fund, and the Prins Bernard Culture Fund in the Netherlands; the VA CSR&D Research Career Scientist Award (Grant No. CX002074 [to FH]) laboratory; and James J. Peters VA Medical Center (Grant Nos. CX001728 , CX001395 , BX003794 , and RX001705 [to FH]). Publisher Copyright: © 2021
(Peer reviewed)