Xu Jiawei, He Guang, Zhu Jingde, Zhou Xinyao, St Clair David, Wang Teng, Xiang Yuqian, Zhao Qingzhu, Xing Qinghe, Liu Yun, Wang Lei, Li Qiaoli, He Lin, Zhao Xinzhi
Children's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China (Drs Xu, Zhou, T. Wang, Xiang, Xing, Liu, L. Wang, Li, L. He and X. Zhao); Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China (Drs Xu, G. He, Zhou, T. Wang, Xiang, Q. Zhao, Xing, Liu, L.Wang, Li, L. He and X. Zhao); Center for Reproductive Medicine, The First Affiliated Hospital of Zhengzhou University, Shanghai, China (Dr Xu); Cancer Epigenetics and Gene Therapy Program, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai, China (Dr Zhu); Department of Mental Health, University of Aberdeen, Scotland (Dr St Clair).
Int J Neuropsychopharmacol. 2014 Oct 31;18(4):pyu054. doi: 10.1093/ijnp/pyu054.
Epidemiological studies have identified prenatal exposure to famine as a risk factor for schizophrenia, and animal models of prenatal malnutrition display structural and functional brain abnormalities implicated in schizophrenia.
The offspring of the RLP50 rat, a recently developed animal model of prenatal famine malnutrition exposure, was used to investigate the changes of gene expression and epigenetic modifications in the brain regions. Microarray gene expression analysis was carried out in the prefrontal cortex and the hippocampus from 8 RLP50 offspring rats and 8 controls. MBD-seq was used to test the changes in DNA methylation in hippocampus depending on prenatal malnutrition exposure.
In the prefrontal cortex, offspring of RLP50 exhibit differences in neurotransmitters and olfactory-associated gene expression. In the hippocampus, the differentially-expressed genes are related to synaptic function and transcription regulation. DNA methylome profiling of the hippocampus also shows widespread but systematic epigenetic changes; in most cases (87%) this involves hypermethylation. Remarkably, genes encoded for the plasma membrane are significantly enriched for changes in both gene expression and DNA methylome profiling screens (p = 2.37×10(-9) and 5.36×10(-9), respectively). Interestingly, Mecp2 and Slc2a1, two genes associated with cognitive impairment, show significant down-regulation, and Slc2a1 is hypermethylated in the hippocampus of the RLP50 offspring.
Collectively, our results indicate that prenatal exposure to malnutrition leads to the reprogramming of postnatal brain gene expression and that the epigenetic modifications contribute to the reprogramming. The process may impair learning and memory ability and result in higher susceptibility to schizophrenia.
流行病学研究已将产前暴露于饥荒确定为精神分裂症的一个风险因素，产前营养不良的动物模型显示出与精神分裂症相关的大脑结构和功能异常。
使用最近开发的产前饥荒营养不良暴露动物模型RLP50大鼠的后代，来研究大脑区域基因表达和表观遗传修饰的变化。对8只RLP50后代大鼠和8只对照大鼠的前额叶皮质和海马进行微阵列基因表达分析。使用MBD-seq来检测产前营养不良暴露对海马DNA甲基化变化的影响。
在前额叶皮质中，RLP50的后代在神经递质和嗅觉相关基因表达方面存在差异。在海马中，差异表达的基因与突触功能和转录调控有关。海马的DNA甲基化组分析也显示出广泛但系统性的表观遗传变化；在大多数情况下（87%），这涉及到高甲基化。值得注意的是，在基因表达和DNA甲基化组分析筛选中，编码质膜的基因在变化方面都显著富集（分别为p = 2.37×10(-9)和5.36×10(-9)）。有趣的是，与认知障碍相关的两个基因Mecp2和Slc2a1显示出显著下调，并且Slc2a1在RLP50后代的海马中发生高甲基化。
总体而言，我们的结果表明产前暴露于营养不良会导致出生后脑基因表达的重编程，并且表观遗传修饰促成了这种重编程。这个过程可能会损害学习和记忆能力，并导致对精神分裂症的易感性增加。
