Nagy C, Suderman M, Yang J, Szyf M, Mechawar N, Ernst C, Turecki G
1] McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada [2] Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada.
1] McGill Centre for Bioinformatics, McGill University, Montreal, QC, Canada [2] Sackler Program for Epigenetics and Developmental Psychobiology, McGill University, Montreal, QC, Canada.
Mol Psychiatry. 2015 Mar;20(3):320-8. doi: 10.1038/mp.2014.21. Epub 2014 Mar 25.
Astrocytes are glial cells specific to the central nervous system and involved in numerous brain functions, including regulation of synaptic transmission and of immune reactions. There is mounting evidence suggesting astrocytic dysfunction in psychopathologies such as major depression, however, little is known about the underlying etiological mechanisms. Here we report a two-stage study investigating genome-wide DNA methylation associated with astrocytic markers in depressive psychopathology. We first characterized prefrontal cortex samples from 121 individuals (76 who died during a depressive episode and 45 healthy controls) for the astrocytic markers GFAP, ALDH1L1, SOX9, GLUL, SCL1A3, GJA1 and GJB6. A subset of 22 cases with consistently downregulated astrocytic markers was then compared with 17 matched controls using methylation binding domain-2 (MBD2) sequencing followed by validation with high-resolution melting and bisulfite Sanger sequencing. With these data, we generated a genome-wide methylation map unique to altered astrocyte-associated depressive psychopathology. The map revealed differentially methylated regions (DMRs) between cases and controls, the majority of which displayed reduced methylation levels in cases. Among intragenic DMRs, those found in GRIK2 (glutamate receptor, ionotropic kainate 2) and BEGAIN (brain-enriched guanylate kinase-associated protein) were most significant and also showed significant correlations with gene expression. Cell-sorted fractions were investigated and demonstrated an important non-neuronal contribution of methylation status in BEGAIN. Functional cell assays revealed promoter and enhancer-like properties in this region that were markedly decreased by methylation. Furthermore, a large number of our DMRs overlapped known Encyclopedia of DNA elements (ENCODE)-identified regulatory elements. Taken together, our data indicate significant differences in the methylation patterns specific to astrocytic dysfunction associated with depressive psychopathology, providing a potential framework for better understanding this disease phenotype.
星形胶质细胞是中枢神经系统特有的神经胶质细胞，参与多种脑功能，包括调节突触传递和免疫反应。越来越多的证据表明，在诸如重度抑郁症等精神病理学中存在星形胶质细胞功能障碍，然而，其潜在的病因机制却知之甚少。在此，我们报告一项两阶段研究，该研究调查了与抑郁性精神病理学中星形胶质细胞标志物相关的全基因组DNA甲基化情况。我们首先对121名个体（76名在抑郁发作期间死亡者和45名健康对照者）的前额叶皮质样本进行星形胶质细胞标志物GFAP、ALDH1L1、SOX9、GLUL、SCL1A3、GJA1和GJB6的特征分析。然后，使用甲基化结合结构域2（MBD2）测序法，将22例星形胶质细胞标志物持续下调的病例子集与17名匹配对照进行比较，随后通过高分辨率熔解和亚硫酸氢盐桑格测序法进行验证。利用这些数据，我们生成了与星形胶质细胞改变相关的抑郁性精神病理学特有的全基因组甲基化图谱。该图谱揭示了病例组和对照组之间的差异甲基化区域（DMR），其中大多数在病例组中显示甲基化水平降低。在基因内DMR中，在GRIK2（离子型红藻氨酸盐2型谷氨酸受体）和BEGAIN（脑富集鸟苷酸激酶相关蛋白）中发现的DMR最为显著，并且还与基因表达呈显著相关性。对细胞分选组分进行了研究，结果表明BEGAIN中甲基化状态具有重要的非神经元作用。功能性细胞分析揭示了该区域中启动子和增强子样特性，这些特性因甲基化而显著降低。此外，我们的大量DMR与已知的DNA元件百科全书（ENCODE）鉴定的调控元件重叠。综上所述，我们的数据表明，与抑郁性精神病理学相关的星形胶质细胞功能障碍特有的甲基化模式存在显著差异，为更好地理解这种疾病表型提供了一个潜在的框架。
