表观遗传时钟调控神经发育参与精神分裂症发病的表观遗传机制研究

DNA甲基化是个体发育和疾病发生的关键表观遗传调控机制。神经系统基因甲基化异常可导致神经发育障碍，是引发精神分裂症的重要原因。神经发育异常的及时发现对精神分裂症的早期防治意义重大。表观遗传时钟是由DNA甲基化衍生的测量组织和细胞生物学年龄的工具，可衡量个体发育进程。预实验基于全基因组甲基化大数据，发现精神分裂症致表观遗传时钟迟滞且差异DNA甲基化注释基因富集于发育相关功能。其中多个基因与神经发育相关，但表观遗传机制不清。本项目提出表观遗传时钟DNA甲基化调控神经发育参与精神分裂症发生发展的假说，并通过整合精神分裂症基因组、转录组、表观组大数据，筛选疾病相关的表观遗传时钟差异DNA甲基化位点及功能基因座，利用SK-N-SH细胞株、小鼠动物行为学模型和散发病例对照人群，阐明疾病相关表观遗传时钟DNA甲基化调控神经发育参与精神分裂症的表观遗传机制，为精神分裂症早期诊断生物标记提供新的科学证据。

DNA methylation is an important epigenetic modification that plays an important role in development and disease. Aberrant DNA methylation of genes in the nervous system can lead to neurodevelopmental disorders and it is an important trigger for schizophrenia. The timely detection of neurodevelopmental abnormalities has great significances for the early prevention and treatment of schizophrenia. The “epigenetic clock” is a DNA methylation-derived measure that can not only predict chronological age but also reveal biological age of various tissues and cells, which measures the progression of development over the life span..In previous studies, we collected a large of genome-wide methylation datasets of whole blood and brain tissue to quantify the epigenetic age of different tissues from individuals with schizophrenia by “epigenetic clock” methods. We found that schizophrenia significantly reduces epigenetic age acceleration in both blood and brain tissue. Meanwhile, the genes related to differentially methylated CpG sites from “epigenetic clock” were significantly enriched in the functions of cell differentiation and tissue development, which indicated that the development process of schizophrenia is blocked, but the mechanism is unclear. Based on this, the current proposal hypothesizes that the DNA methylation from “epigenetic clock” is a key regulatory mechanism during neurodevelopment involved in the etiologic developments of schizophrenia. Firstly, cross-validation and characterization of disease-related alterations of DNA methylation in “epigenetic clock” will be examined in DNA methylation datasets between postmortem brain tissues and peripheral blood. Secondly, the study will screen functional regulatory element and genes from disease-related epigenetic clock DNA methylation sites by integrating of genome wide association study (GWAS), transcriptome, and epigenetic from schizophrenia. Finally, biological mechanisms of disease-related epigenetic clock DNA methylation involved in neurodevelopment underlying the schizophrenia will be further analyzed in a neuroblast-like SK-N-SH cell line, a mouse animal behavioural model, and an independent sporadic case-control cohort..The current proposal takes epigenetic age as the entry point to identify novel biomarkers for in vivo monitoring the neurodevelopment of schizophrenia, and provide novel evidences for early diagnosis of schizophrenia.