Wei Hui, Yuan Yanbo, Zhu Caiyun, Ma Mingjie, Yang Fude, Lu Zheng, Wang Chuanyue, Deng Hong, Zhao Jingping, Tian Runhui, Zhu Wanwan, Shen Yan, Yu Xin, Xu Qi
State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China.
Neuroscience Center, Chinese Academy of Medical Sciences, Beijing, China.
Schizophr Bull Open. 2022 Nov 9;5(1):sgac047. doi: 10.1093/schizbullopen/sgac047. eCollection 2024 Jan.
Environmental stressors may influence immune surveillance in B lymphocytes and stimulate autoimmune responses via epigenetic DNA methylation modifications in schizophrenia (SCZ).
A total of 2722, Chinese Han origin subjects were recruited in this study (2005-2011), which included a discovery follow-up cohort with 40 remitters of SCZ (RSCZ), 40 nonremitters of SCZ (NRSCZ), and 40 controls (CTL), and a replication follow-up cohort (64 RSCZ, 16 NRSCZ, and 84 CTL), as well as a case-control validation cohort (1230 SCZ and 1208 CTL). Genomic DNA methylation, target gene mRNA transcripts, and plasma autoantibody levels were measured across cohorts.
We found extensive differences in global DNA methylation profiles between RSCZ and NRSCZ groups, wherein differential methylation sites (DMS) were enriched with immune cell maturation and activation in the RSCZ group. Out of 2722 participants, the foremost DMS cg14341177 was hyper-methylated in the SCZ group and it inhibited the alternative splicing of its target gene and may have increased its autoantigen exposure, leading to an increase in plasma anti-BICD2 IgG antibody levels. The levels of cg14341177 methylation and anti-BICD2 IgG decreased significantly in RSCZ endpoint samples but not in NRSCZ endpoint samples. There are strong positive correlations between cg14341177 methylation, anti-BICD2 IgG, and positive and negative syndrome scale (PANSS) scores in the RSCZ groups, but not in the NRSCZ groups.
These data suggest that abnormal DNA methylation could affect autoreactive responses in SCZ, and that cg14341177 methylation and anti-BICD2 IgG levels may potentially serve as useful biomarkers.
环境应激源可能影响B淋巴细胞的免疫监视，并通过精神分裂症（SCZ）中表观遗传DNA甲基化修饰刺激自身免疫反应。
本研究共招募了2722名中国汉族受试者（2005年至2011年），包括一个发现随访队列，其中有40名SCZ缓解者（RSCZ）、40名SCZ未缓解者（NRSCZ）和40名对照（CTL），以及一个重复随访队列（64名RSCZ、16名NRSCZ和84名CTL），还有一个病例对照验证队列（1230名SCZ和1208名CTL）。对各队列的基因组DNA甲基化、靶基因mRNA转录本和血浆自身抗体水平进行了检测。
我们发现RSCZ组和NRSCZ组之间的全基因组DNA甲基化谱存在广泛差异，其中RSCZ组的差异甲基化位点（DMS）富含免疫细胞成熟和激活相关基因。在2722名参与者中，最重要的DMS cg14341177在SCZ组中呈高甲基化状态，它抑制了其靶基因的可变剪接，并可能增加了其自身抗原暴露，导致血浆抗BICD2 IgG抗体水平升高。cg14341177甲基化水平和抗BICD2 IgG在RSCZ终点样本中显著下降，但在NRSCZ终点样本中未下降。在RSCZ组中，cg14341177甲基化、抗BICD2 IgG与阳性和阴性症状量表（PANSS）评分之间存在强正相关，但在NRSCZ组中不存在。
这些数据表明，异常的DNA甲基化可能影响SCZ中的自身反应性，并且cg14341177甲基化和抗BICD2 IgG水平可能潜在地作为有用的生物标志物。
