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 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.

中文翻译：

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年龄、脑区、情绪障碍病理学和个体间因素对人类小胶质细胞甲基化组的贡献

背景

转录组研究揭示了与年龄、疾病和区域相关的小胶质细胞表型，反映了发育、衰老、中枢神经系统稳态和病理过程中小胶质细胞功能的变化。促成这些转录组变化的分子机制在很大程度上是未知的。本研究的目的是描述人类小胶质细胞的 DNA 甲基化景观以及导致小胶质细胞甲基化组变化的因素。我们假设年龄和大脑区域都会对小胶质细胞中的 DNA 甲基化产生很大影响。

方法

使用全基因组甲基化阵列分离和分析来自 22 名供体（包括 1 名精神分裂症患者、13 名患有情绪障碍病理学的患者和 8 名对照受试者）的四个不同脑区的死后脑组织的小胶质细胞。

结果

我们发现人类小胶质细胞具有不同于大块脑组织和神经元的甲基化谱，而年龄解释了很大一部分变异。此外，我们发现个体间因素对小胶质细胞甲基化景观的影响比大脑区域大得多，这也在转录组水平上观察到。在我们的探索性分析中，我们发现了与疾病状态（情绪障碍与控制）相关的各种差异甲基化区域。这包括与小胶质细胞中的基因表达以及骨髓细胞功能或神经精神疾病相关的差异甲基化区域。

结论

尽管基于相对较小的样本，但这些发现表明小胶质细胞的甲基化谱对个体间的变异有反应，因此在转录组水平观察到的小胶质细胞的异质性中起重要作用。