Epigenetic regulation of brain region-specific microglia clearance activity

The rapid elimination of dying neurons and non-functional synapses in the brain is carried out by microglia, the resident myeloid cells of the brain. Here we show that microglia clearance activity in the adult brain is regionally regulated and depends on the rate of neuronal attrition. Cerebellar, but not striatal or cortical, microglia exhibited high levels of basal clearance activity, which correlated with an elevated degree of cerebellar neuronal attrition. Exposing forebrain microglia to apoptotic cells activated gene expression programs supporting clearance activity. We provide evidence that the Polycomb repressive complex 2 (PRC2) epigenetically restricts the expression of genes that support clearance activity in striatal and cortical microglia. Loss of PRC2 led to the aberrant activation of a microglia clearance phenotype, which triggers changes in neuronal morphology and behavior. Our data highlight a key role of epigenetic mechanisms in preventing microglia-induced neuronal alterations that are frequently associated with neurodegenerative and psychiatric diseases. Microglial RNAs or nuclei were isolated based on the eGFP-L10a expression of ribosomes and fluorescence of newly formed ribosomes in the microglia nucleoli, respectively

大脑中濒死神经元与无功能突触的快速清除，由脑内驻留髓系细胞——小胶质细胞（microglia）执行。本研究证实，成年大脑内的小胶质细胞清除活性受区域特异性调控，且依赖于神经元损耗速率。小脑小胶质细胞（而非纹状体或皮层小胶质细胞）展现出高水平的基础清除活性，该活性与小脑神经元的高损耗程度呈正相关。将前脑小胶质细胞暴露于凋亡细胞中，可激活支持其清除功能的基因表达程序。本研究提供证据表明，多梳抑制复合体2（Polycomb repressive complex 2, PRC2）通过表观遗传机制，抑制纹状体与皮层小胶质细胞中支持清除活性的基因表达。PRC2功能缺失会异常激活小胶质细胞的清除表型，进而引发神经元形态改变与行为异常。本研究数据凸显了表观遗传机制在预防小胶质细胞介导的神经元改变中的关键作用——这类改变常与神经退行性及精神类疾病密切相关。本研究分别基于核糖体的eGFP-L10a表达，以及小胶质细胞核仁中新形成核糖体的荧光信号，分离获取了小胶质细胞的RNA或细胞核。