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Epigenetic profiling of human brain differential DNA methylation networks in schizophrenia

机译：精神分裂症中人脑差异DNA甲基化网络的表观遗传学分析

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Background Epigenetics of schizophrenia provides important information on how the environmental factors affect the genetic architecture of the disease. DNA methylation plays a pivotal role in etiology for schizophrenia. Previous studies have focused mostly on the discovery of schizophrenia-associated SNPs or genetic variants. As postmortem brain samples became available, more and more recent studies surveyed transcriptomics of the diseases. In this study, we constructed protein-protein interaction (PPI) network using the disease associated SNP (or genetic variants), differentially expressed disease genes and differentially methylated disease genes (or promoters). By combining the different datasets and topological analyses of the PPI network, we established a more comprehensive understanding of the development and genetics of this devastating mental illness. Results We analyzed the previously published DNA methylation profiles of prefrontal cortex from 335 healthy controls and 191 schizophrenic patients. These datasets revealed 2014 CpGs identified as GWAS risk loci with the differential methylation profile in schizophrenia, and 1689 schizophrenic differential methylated genes (SDMGs) identified with predominant hypomethylation. These SDMGs, combined with the PPIs of these genes, were constructed into the schizophrenic differential methylation network (SDMN). On the SDMN, there are 10 hypermethylated SDMGs, including GNA13, CAPNS1, GABPB2, GIT2, LEFTY1, NDUFA10, MIOS, MPHOSPH6, PRDM14 and RFWD2. The hypermethylation to differential expression network (HyDEN) were constructed to determine how the hypermethylated promoters regulate gene expression. The enrichment analyses of biochemical pathways in HyDEN, including TNF alpha, PDGFR-beta signaling, TGF beta Receptor, VEGFR1 and VEGFR2 signaling, regulation of telomerase, hepatocyte growth factor receptor signaling, ErbB1 downstream signaling and mTOR signaling pathway, suggested that the malfunctioning of these pathways contribute to the symptoms of schizophrenia. Conclusions The epigenetic profiles of DNA differential methylation from schizophrenic brain samples were investigated to understand the regulatory roles of SDMGs. The SDMGs interplays with SCZCGs in a coordinated fashion in the disease mechanism of schizophrenia. The protein complexes and pathways involved in SDMN may be responsible for the etiology and potential treatment targets. The SDMG promoters are predominantly hypomethylated. Increasing methylation on these promoters is proposed as a novel therapeutic approach for schizophrenia.
机译：背景精神分裂症的表观遗传学提供了有关环境因素如何影响疾病遗传结构的重要信息。 DNA甲基化在精神分裂症的病因学中起着关键作用。先前的研究主要集中在精神分裂症相关SNP或遗传变异的发现上。随着死后脑样本的获得，越来越多的近期研究调查了疾病的转录组学。在这项研究中，我们使用疾病相关的SNP（或遗传变异），差异表达的疾病基因和差异甲基化的疾病基因（或启动子）构建了蛋白质-蛋白质相互作用（PPI）网络。通过结合PPI网络的不同数据集和拓扑分析，我们对这种毁灭性精神疾病的发展和遗传学有了更全面的了解。结果我们分析了335位健康对照者和191位精神分裂症患者先前发表的前额叶皮层的DNA甲基化谱。这些数据集揭示了2014年CpGs被鉴定为GWAS风险基因座，其精神分裂症的甲基化水平有所差异，还有1689个精神分裂症的甲基化差异化基因（SDMG）被识别为主要的甲基化不足。这些SDMG与这些基因的PPI相结合，被构建为精神分裂症差异甲基化网络（SDMN）。在SDMN上，有10个超甲基化SDMG，包括GNA13，CAPNS1，GABPB2，GIT2，LEFTY1，NDUFA10，MIOS，MPHOSPH6，PRDM14和RFWD2。构建到差异表达网络的高甲基化网络（HyDEN），以确定高甲基化的启动子如何调节基因表达。 HyDEN中生化途径的丰富分析，包括TNFα，PDGFR-beta信号，TGFβ受体，VEGFR1和VEGFR2信号，端粒酶的调节，肝细胞生长因子受体信号，ErbB1下游信号和mTOR信号通路，提示这些途径有助于精神分裂症的症状。结论研究了精神分裂症脑样本中DNA差异甲基化的表观遗传概况，以了解SDMGs的调节作用。 SDMGs与SCZCGs在精神分裂症的发病机理中以协调的方式相互作用。 SDMN中涉及的蛋白质复合物和途径可能是造成病因和潜在治疗目标的原因。 SDMG启动子主要是低甲基化的。这些启动子上增加的甲基化被提议作为精神分裂症的一种新型治疗方法。

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