The DNA Methylome and Transcriptome of Different Brain Regions in Schizophrenia and Bipolar Disorder

Extensive changes in DNA methylation have been observed in schizophrenia (SC) and bipolar disorder (BP), and may contribute to the pathogenesis of these disorders. Here, we performed genome-scale DNA methylation profiling using methylated DNA immunoprecipitation followed by sequencing (MeDIP-seq) on two brain regions (including frontal cortex and anterior cingulate) in 5 SC, 7 BP and 6 normal subjects. Comparing with normal controls, we identified substantial differentially methylated regions (DMRs) in these two brain regions of SC and BP. To our surprise, different brain regions show completely distinct distributions of DMRs across the genomes. In frontal cortex of both SC and BP subjects, we observed widespread hypomethylation as compared to normal controls, preferentially targeting the terminal ends of the chromosomes. In contrast, in anterior cingulate, both SC and BP subjects displayed extensive gain of methylation. Notably, in these two brain regions of SC and BP, only a few DMRs overlapped with promoters, whereas a greater proportion occurs in introns and intergenic regions. Functional enrichment analysis indicated that important psychiatric disorder-related biological processes such as neuron development, differentiation and projection may be altered by epigenetic changes located in the intronic regions. Transcriptome analysis revealed consistent dysfunctional processes with those determined by DMRs. Furthermore, DMRs in the same brain regions from SC and BP could successfully distinguish BP and/or SC from normal controls while differentially expressed genes could not. Overall, our results support a major role for brain-region-dependent aberrant DNA methylation in the pathogenesis of these two disorders.

研究已在精神分裂症（schizophrenia, SC）与双相情感障碍（bipolar disorder, BP）中发现广泛的DNA甲基化改变，此类改变或参与两类疾病的发病机制。本研究采用甲基化DNA免疫共沉淀联合测序（methylated DNA immunoprecipitation followed by sequencing, MeDIP-seq）技术，对5例精神分裂症患者、7例双相情感障碍患者及6例正常对照的两个脑区——包括额叶皮层（frontal cortex）与前扣带回皮层（anterior cingulate）——开展全基因组DNA甲基化谱分析。与正常对照相比，本研究在精神分裂症与双相情感障碍患者的上述两个脑区中鉴定出大量差异甲基化区域（differentially methylated regions, DMRs）。令人意外的是，不同脑区的差异甲基化区域在基因组中的分布模式完全不同。在精神分裂症与双相情感障碍患者的额叶皮层中，相较于正常对照，我们观察到广泛的低甲基化现象，且此类低甲基化区域优先富集于染色体末端。与之相反，在前扣带回皮层中，精神分裂症与双相情感障碍患者则呈现出广泛的甲基化水平升高现象。值得注意的是，在两类患者的上述两个脑区中，仅有少量差异甲基化区域与启动子区域重叠，而绝大多数差异甲基化区域分布于内含子及基因间区。功能富集分析显示，与精神疾病相关的重要生物学过程——如神经元发育、分化及投射——可能因内含子区域的表观遗传改变而发生异常。转录组分析结果显示，其异常生物学过程与差异甲基化区域分析得到的结果一致。此外，基于精神分裂症与双相情感障碍患者同一脑区的差异甲基化区域，可以有效区分精神分裂症、双相情感障碍患者与正常对照，而差异表达基因则无法实现这一区分效果。综上，本研究结果表明，脑区特异性的DNA甲基化异常在精神分裂症与双相情感障碍的发病机制中发挥重要作用。